Drug Metabolism in Chronic Kidney Disease

C H A P T E R

63 Drug Metabolism in Chronic Kidney Disease Bradley L. Urquharta, Thomas D. Nolinb a

Department of Physiology and Pharmacology and Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; bCenter for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics and Department of Medicine Renal Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, PA, United States

Abstract Patients with chronic kidney disease (CKD), which is typically accompanied by several comorbid conditions, require multiple medications on a daily basis to treat their underlying disease. Decreased renal excretion of drugs is a welldocumented consequence of CKD. In addition, there now is abundant evidence indicating that the function of drug metabolizing enzymes and transporters, which collectively determine net nonrenal drug clearance, is differentially altered in CKD. Basic principles of drug metabolism and transport are reviewed and discussed in the context of drug therapy in patients with CKD. Evidence is presented from preclinical to clinical studies, and important clinical examples are highlighted.

SCOPE OF THE PROBLEM The prevalence of chronic kidney disease (CKD) in adults between 2011 and 2014 was 14.8% of the US population, and at the end of 2015 there were over 700,000 patients with end-stage renal disease (ESRD).1 The number of patients progressing to ESRD continues to rise by approximately 20,000 cases per year, and there are now over 1 million patients globally that have ESRD and are treated with renal replacement therapies such as dialysis.2 CKD is commonly accompanied by several comorbidities, including diabetes, hypertension, anemia, and cardiovascular disease. These comorbidities significantly increase the risk of serious events and decrease life expectancy. For example, the life expectancy at age 55 is reduced from 19.9 years with normal or slightly reduced kidney function to 5.6 years with severe CKD.3 The increased risk of adverse events is at least partly mediated by decreased clearance of uremic

Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00063-2

toxins, molecules that accumulate in the blood of CKD patients as their kidney function declines.4e6 CKD patients are prescribed a disproportionately high number of medications to treat their underlying kidney disease and the large number of comorbidities. For example, ESRD patients treated with maintenance hemodialysis (HD) have a median daily pill burden of 19, with one quarter of patients exceeding 25 pills per day.7 Collectively, HD patients take an average of 12 different medications in an attempt to control their various comorbidities.8 A consequence of both their CKD and large pill burden is heightened risk for adverse drug events. This is highlighted by a report that indicates there is one medication-related problem for every 2.7 medication exposures in maintenance HD patients.9 Dosing of medications in CKD continues to be a challenge, with rates of inappropriate dosing reported to be as high as 68 per 100 prescriptions for antibiotics.10 Changes in the pharmacokinetics of many drugs induced by kidney disease further complicates pharmacotherapy in CKD. The kidney is the primary organ responsible for drug excretion so it is not surprising that decreased kidney function decreases the excretion of many drugs. Drugs are typically designed and tested for use in healthy patients with normal kidney function with minimal to no testing in patients with impaired kidney function. Traditional strategies for prescribing drugs in CKD patients include selection of medications that exhibit minimal to no renal excretion under the premise that they may be administered in normal unadjusted doses, or using nomograms or equations to adjust the dosing of drugs that are excreted by the kidney. The revised Food and Drug Administration (FDA) guidance for industry on pharmacokinetics in patients with impaired kidney function highlights the need for

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© 2020 Elsevier Inc. All rights reserved.

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63. DRUG METABOLISM IN CHRONIC KIDNEY DISEASE

pharmacokinetic studies in CKD patients.11 An additional important consideration is the impact of dialysis on drug clearance and pharmacokinetics. It is clear that dialysis does not replace the functioning kidney as several highly protein bound substrates removed via renal tubular secretion are inefficiently removed by dialysis, and dialytic clearance can vary substantially among drugs from within the same class.12 In addition to directly impacting renal drug clearance, CKD has pronounced effects on nonrenal clearance of drugs. Nonrenal drug clearance comprises hepatic and extrahepatic metabolism (collectively metabolic clearance) and drug transport. The nonrenal clearance of many drugs is altered in patients with impaired kidney function, often translating into clinically relevant changes in systemic exposure (Table 63.1). Hepatic metabolism and transport are the largest contributors to

nonrenal drug clearance, although other organs such as the intestine, heart, and lung contribute to varying degrees. Changes in hepatic metabolism induced by CKD are especially important to consider because approximately 73% of drugs undergo metabolism prior to being eliminated.13 Similarly, hepatic transporters are essential for delivering substrate drugs to the liver for subsequent metabolism and/or transporter-mediated biliary excretion. The objective of this chapter is to highlight CKDmediated changes to drug metabolism and transport and to discuss the implications of these changes on the pharmacokinetics of drugs in CKD patients. Several excellent review articles have also addressed this area.14e26

DRUG METABOLISM AND TRANSPORT TABLE 63.1

Selected Drugs With Evidence of Altered Nonrenal Clearance in Humans With Chronic Kidney Disease

Acyclovir

Ciprofloxacin

Ketorolac

Propoxyphene

Alfuzosin

Cyclophosphamide

Lanthanum

Propranolol

Aliskiren

Darifenacin

Lidocaine

Quinapril

Aprepitant

Desmethyldiazepam Lomefloxacin

Raloxifene

Aztreonam

Dextromethorphan

Losartan

Ranolazine

Bufurolol

Diacerein

Lovastatin

Reboxetine

Bupropion

Didanosine

Metoclopromide Repaglinide

Captopril

Dihydrocodeine

Metoprolol

Rosuvastatin

Carvedilol

Doxorubicin

Midazolam

Roxithromycin

Caspofungin

Duloxetine

Minoxidil

Sildenafil

Cefepime

Encainide

Morphine

Simvastatin

Cefmenoxime Eprosartan

Moxalactam

Solifenacin

Cefmetazole

Erythromycin

Naltrexone

Sparfloxacin

Cefonicid

Felbamate

Nebivolol

Tacrolimus

Cefotaxime

Fexofenadine

Nefopam

Tadalafil

Cefsulodin

Fluorouracil

Nicardipine

Telithromycin

Ceftibuten

Fluvastatin

Nimodipine

Valsartan

Ceftizoxime

Guanadrel

Nitrendipine

Vancomycin

Ceftriaxone

Idarubicin

Nortriptyline

Vardenafil

Cerivastatin

Imatinib

Oxcarbazepine

Verapamil

Cibenzoline

Imipenem

Oxprenolol

Warfarin

Cilastatin

Isoniazid

Paroxetine

Zidovudine

Cimetidine

Ketoprofen

Procainamide

Adapted in part from references 24, 26, and 90.

The majority of medications are xenobiotics, or substances foreign to the human body. Organs such as the liver, intestine, kidney, and lung have evolved a complex network of enzymes and transporters that facilitate systemic exposure and elimination of xenobiotics from the body. Drug-metabolizing enzymes are classified into phase 1 (oxidation, reduction, hydrolysis) or phase 2 (conjugation) reactions (see Figure 63.1). Drugmetabolizing enzymes usually convert lipophilic drugs into more polar metabolites to facilitate their excretion. Drug transporters are expressed on cell membranes and mediate the uptake and efflux of drugs (Figure 63.1). The most important uptake transporters that impact drug disposition are the solute carrier (SLC) transporters. SLC transporters are typically facilitated transporters and ion-coupled secondary active transporters. There are 43 known SLC families and approximately 300 SLC transporters, many of which are determinants of drug absorption and disposition.27 Similarly, the ATP-binding cassette (ABC) family of transporters is the most relevant efflux transporter family for drug disposition. ABC transporters are largely primary active transporters that use ATP hydrolysis as an energy source to pump substrates out of cells, often against a concentration gradient. There are 49 known ABC genes and 7 families of ABC transporters.27 Collectively, drug-metabolizing enzymes and transporters are key mediators of both renal and nonrenal drug clearance and act in a concerted manner to determine the pharmacokinetics of drugs. A change in the expression or activity of drug metabolizing enzymes or transporters can profoundly alter the pharmacokinetics of substrate drugs. The interplay between drug metabolizing enzymes and drug transporters is demonstrated in Figure 63.1.

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FIGURE 63.1 The interplay between drug metabolism and transport. Drugs may enter the cell by passive diffusion (not shown) or via an uptake transporter (depicted by blue sphere). Once inside the cell, the drug may be 1) removed from the cell by an efflux transporter (purple sphere) or metabolized by phase I (oxidation, reduction, hydrolysis) or phase II (conjugation) drug-metabolizing enzymes. Although drugs are typically metabolized first by phase I enzymes prior to phase II metabolism, some drugs are directly metabolized by phase II enzymes. Metabolites (phase I or II) may also be subject to efflux from the cell. Images used to generate this figure were modified from Servier Medical Art, licensed under Creative Commons Attribution 3.0 Generic License, http://smart.servier.com/.

DRUG METABOLISM IN PRECLINICAL MODELS OF CKD The earliest reports of altered drug metabolism in CKD were published in the 1970s and 1980s in experimental (mostly rat) models of CKD.28e31 These pioneering studies used probes of global cytochrome P450 activity (i.e. substrates metabolized by multiple enzymes), such as aminopyrine, acetanilide, and p-nitroanisol. Experimental kidney disease was typically induced in these studies by a 5/6 nephrectomy. In this procedure, 2/3 of the kidney mass is surgically resected and one week later a complete nephrectomy is performed, resulting in only 1/6 of the total kidney mass remaining. Although the remaining kidney mass undergoes hyperfiltration in an attempt to compensate for the nephron loss, the animals ultimately experience kidney disease as evidenced by increases in serum creatinine concentration (S[Cr]) and blood urea nitrogen (BUN). These early preclinical studies demonstrated a 32% reduction in total cytochrome P450 (CYP) content in CKD animals along with a 35%, 37%, and 31% decrease in the CYP-mediated metabolism of aminopyrine, p-nitroanisol, and acetanilide, respectively,31 substrates that are broad probes of CYP enzymes. For

example, antipyrine is metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4 in humans.32 Accordingly, these studies suggested that hepatic drug metabolism is decreased in CKD but provided little information on the specific pathways that are altered by kidney disease. Subsequent research focused on delineating the specific metabolic pathways altered in CKD. Uchida and colleagues used a 5/6 nephrectomy model to evaluate the effect of CKD on hepatic drug-metabolizing enzymes.33 A negative correlation between BUN and cytochrome P450 content as well as multiple hepatic specific activities (e.g. aminopyrine demethylase and d-aminolevulinic acid synthetase) was observed. In addition, hepatic Cyp2c6, Cyp2c11, and Cyp3a2 were downregulated in CKD (note lower case letters in Cyps represent rodent). Leblond, Pichette, and colleagues, who systematically investigated the effect of CKD on drug metabolism in elegant studies that spanned over a decade,34e40 demonstrated that total hepatic CYP content was negatively correlated with creatinine clearance. Although there was no change in the activity of Cyp1a or Cyp2d enzymes, a pronounced decrease in the mRNA and protein expression of Cyp2c11, Cyp3a1 (Cyp3a23), and Cyp3a2 in the 5/6

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63. DRUG METABOLISM IN CHRONIC KIDNEY DISEASE

nephrectomy rat model was shown.39 Collectively, these represent the rat orthologs of human CYP2C9 and CYP3A4, respectively. The in vivo relevance of these observations was also reported. Specifically, a caffeine breath test (Cyp1a probe) revealed no change in Cyp1a metabolic activity in CKD animals in vivo compared to controls, confirming ex vivo observations.40 Similarly, in vivo breath tests for aminopyrine (Cyp2c11 probe) and erythromycin (Cyp3a probe) revealed a 35% decrease in the activities of Cyp2c11 and Cyp3a in CKD animals compared to controls, again confirming ex vivo microsomal studies. Although this collection of work clearly indicates hepatic drug metabolism is significantly impaired in severe kidney disease induced by 5/6 nephrectomy, it raised the question of whether drug metabolism is impacted in earlier stages of disease. Velenosi and colleagues used a modified surgical/vessel ligation technique to generate a model of moderate kidney impairment41 that demonstrated even moderate kidney disease (1.7-fold increase in S[Cr]) was able to induce a greater than 60% decrease in Cyp2c11 and Cyp3a2 mRNA and protein expression. In addition, the catalytic activity of midazolam (Cyp3a) and testosterone (Cyp2c11 and Cyp3a) were significantly decreased in both moderate and severe kidney disease. There was an exponential decline in hepatic drug metabolizing enzyme activity as kidney disease progressed, suggesting that a small change in kidney function has a profound impact on drug metabolism.41 The dietary adenine model of CKD, which has gained popularity as it provides less variability in degree of kidney disease,42 has also been used to study the impact of CKD on drug metabolism. Similar to the 5/6 nephrectomy model, adenine-induced CKD causes a pronounced decrease in hepatic Cyp2c11 and Cyp3a2 expression and activity in rats, but no significant differences in hepatic Cyp1a or Cyp2d.43 CKD also elicits changes in extra-hepatic drug metabolism. Although the liver is the body’s primary metabolic organ, substantial drug metabolism occurs in both intestinal enterocytes and renal tubular cells. Expression of Cyp1a1 and Cyp3a2 mRNA and protein are significantly downregulated in rats with CKD.44 Moreover, enzymatic activity assays using ethoxyresorufin O-dealkylation (Cyp1a) and erythromycin demethylation (Cyp3a) confirm that Cyp1a and Cyp3a activity is decreased. These changes suggest that altered intestinal drug metabolism in CKD may impact the bioavailability of drugs. Cytochrome P450 expression was also evaluated in the remnant kidney from rats that underwent 5/6 subtotal nephrectomy.45 In contrast to liver and intestine, there was no change in renal

Cyp3a2, but Cyp1a1 was significantly downregulated in CKD compared to control.44 Although cytochrome P450s are the most widely studied phase I drug metabolizing enzymes, hepatic reductases are also important phase I drug metabolizing enzymes relevant to drug disposition. One of the most important and widely used drugs impacted by hepatic drug reduction is the anticoagulant warfarin, which is used extensively in patients with CKD. In addition to CYP-mediated phase I metabolism, the acetonyl functional group of warfarin is reduced by hepatic reductases to form warfarin alcohols. The reduction of warfarin generates a second chiral center, such that two diastereoisomers of warfarin alcohols may be generated: warfarin alcohol 1 (RS/SR) and warfarin alcohol 2 (RR/SS). Warfarin reduction is mediated by the cytosolic enzymes carbonyl reductase 1 (CBR1) and aldo-keto reductase family 1 member C3 (AKR1C3) and by the microsomal enzyme 11 b-hydroxysteroid dehydrogenase 1 (11 b-HSD1). Alshogran and colleagues used the 5/6 nephrectomy model of CKD to evaluate the expression and activity of hepatic reductase enzymes,46 and demonstrated that the mRNA expression of CBR1, AKR1C3, and 11 b-HSD1 were downregulated by 34%, 93%, and 35%, respectively, in CKD compared to controls. Similarly, protein expression of CBR1, AKR1C18 (encoded by the AKR1C3 gene), and 11 b-HSD1 were downregulated by 43%, 76%, and 70% in CKD compared to controls, respectively. The downregulation of these reductases resulted in a 39% decreased formation of warfarin alcohol 1 in the cytosol and a 43% decrease in microsomes from CKD rats compared to sham controls. Phase II drug-metabolizing enzymes serve to conjugate drugs, typically by adding endogenous substances such as glutathione, sulfate, glycine, or glucuronic acid that make the parent drug more polar and/or less toxic (Figure 63.1). The predominant phase II drugmetabolizing enzymes include acetylation (by N-acetyltransferases; NAT), glucuronidation (by uridine 50 -diphospho glucuronosyltransferases; UGT), methylation (by thiopurine methyltransferases; TPMT), and conjugation with glutathione (glutathione Stransferases; GST). Although the 5/6 nephrectomy model of CKD shows no difference in expression or activity in the major UGT enzymes,47 pronounced differences in hepatic acetylation have been described in this model.48 Specifically, a 33% and 50% decrease in Nat1 and Nat2 expression, respectively, is apparent in CKD rats compared to controls. In addition, there is a 50% reduction in Nat2-mediated acetylation of p-aminobenzoic acid in CKD rat liver cytosol compared to controls.

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FIGURE 63.2 Hepatic drug metabolism and transport pathways. Hepatic sinusoids within the liver connect the portal and hepatic circulation and facilitate the formation of bile. The hepatocytes are the primary functional cells in the liver. In the context of drug therapy, drug can be taken up in hepatocytes by uptake transporters (blue spheres). Once within the cell, drugs can be metabolized by phase I (e.g. CYPs) or phase II drugmetabolizing enzymes. Parent drug or metabolite may be removed from the hepatocyte into the blood or excreted into the bile via efflux transporters (purple sphere). Representative transporters and enzymes are shown for reference. Note this is not a complete list. Images used to generate this figure were modified from Servier Medical Art, licensed under Creative Commons Attribution 3.0 Generic License, http://smart.servier.com/.

DRUG METABOLISM IN HUMANS WITH CKD The impact of CKD on drug metabolism in humans is complex, largely owing to the multiple enzymes that metabolize drugs and the complex interplay between drug-metabolizing enzymes and drug transporters (Figure 63.1). The most common approach to assessing drug metabolism in patients with kidney disease is to evaluate the pharmacokinetic parameter clearance (CL). Clearance is the volume of blood (or plasma) from which a substance is removed per unit time. Oral drug clearance is calculated as: CLoral ¼ CL=F ¼ dose  F=AUC where F ¼ bioavailability and AUC ¼ the area under the plasma concentration time curve. In general, oral drug clearance can be considered the sum of renal clearance, hepatic clearance, and clearance from other routes as follows: CLoral ¼ CLrenal þ CLhepatic þ CLother For highly metabolized drugs with a fractional excretion less than 10%, a change in oral clearance is typically assumed to be a change in hepatic clearance because the drug is minimally excreted in the urine and usually other clearance routes (e.g. respiratory and sweat) contribute minimally to total oral clearance.

This is commonly termed nonrenal clearance (CLNR) and refers to clearance by all routes other than the kidney. As described above, multiple enzymes metabolize many drugs and many are also subjected to hepatic transport (Figure 63.2). For these reasons, it is often difficult to link changes in clearance to a specific pathway (e.g. a specific cytochrome P450 isozyme). Fortunately, there are a number of fairly specific probe substrates that have been characterized that allow direct phenotypic characterization of specific metabolic pathways. These include bupropion (CYP2B6), warfarin (CYP2C9), mephenytoin (CYP2C19), sparteine (CYP2D6), midazolam (CYP3A4), and chlorzoxazone (CYP2E1). The function of several cytochrome P450 enzymes has been studied in humans with CKD using these and other probe substrates and is summarized in Table 63.2.

CYP2B6 CYP2B6 is highly expressed in human liver and metabolizes several antidepressants, anticonvulsants, and chemotherapeutic agents. The antidepressant bupropion is extensively metabolized by CYP2B6 and is the most widely used probe of this CYP isozyme. In an open-label pharmacokinetic study, healthy controls and CKD patients (mean eGFR 30.9 mL/min/1.73 m2) were given a single 150 mg oral dose of sustained release

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63. DRUG METABOLISM IN CHRONIC KIDNEY DISEASE

Impact of Chronic Kidney Disease (CKD) on Drug Metabolizing Enzymes in Humans

Enzyme

Probe

Effect of CKD

Interpretation

CYP2B6

Bupropion

[AUC, YCL/F

Y activity in CKD

CYP2C9

Warfarin

YS/R warfarin ratio

Y activity in CKD

CYP2C19

Mephenytoin

¼AUC, ¼CL/F

No Change in CKD

CYP2D6

Sparteine

Unclear

¼ or Y activity in CKD

Dextromethorphan

Unclear

¼ or Y activity in CKD

Nebivolol

[AUC, YCL/F

Y activity in CKD

CYP2E1

Chlorzoxazone

¼ CL

No Change in CKD

CYP3A4

Erythromycin

YBreath test

Y activity in CKD*

YCL

Y activity in CKD*

Oral

¼ AUC, CL/F

No change in CKD

IV

[AUC, YCL/F, ¼t1/2

No change in CKD or modest Y

Doxorubicin

[AUC, YCL

Y activity in CKD

Idarubicin

[AUC, YCL

Y activity in CKD

NAT2

Isoniazid

YCL

Y activity in CKD

UGT1A3 & UGT2B7

Morphine

[AUC, YCL

Y activity in CKD

Midazolam

CBR1 & AKR1C3

* Also extensively transported so unclear if changes are related to altered transport, metabolism, or both.

bupropion. CKD patients had a 126% increase in the AUC and a 63% decrease in CL/F.49 In a different study, patients with biopsy confirmed glomerular disease (lupus nephritis or antineutrophil associated [ANCA] vasculitis) received a single oral 150 mg dose of sustained release bupropion.50 Patients with glomerular disease had a twofold increase in bupropion AUC and CL/F was approximately half compared to subjects without glomerular disease. Collectively, these two studies suggest that CYP2B6 activity is decreased in patients with kidney disease.

metabolized by CYP2C9 into multiple hydroxylated metabolites. The ratio of S-warfarin to R-warfarin is used as a probe of CYP2C9 activity in patients. The S/R-warfarin ratio is increased by 51% in ESRD patients compared to controls, suggesting that hepatic CYP2C9 activity is decreased in kidney disease.51 This finding is consistent with decreased hepatic expression and activity of rat CYP2C11 (generally considered the rat ortholog of human CYP2C9) in CKD.39e41,43

CYP2C19 CYP2C9 CYP2C9 is highly expressed in human liver and is responsible for the metabolism of approximately 13% of the most commonly prescribed drugs.13 Warfarin is an anticoagulant drug used to prevent blood clot formation and migration. Warfarin is a widely used medication in CKD patients for treatment of atrial fibrillation, embolism, and thrombosis and acts by inhibiting vitamin K reduction. It is a racemic mixture of two active enantiomers. The two enantiomers are differentially metabolized by hepatic CYP enzymes. Although R-warfarin is metabolized by multiple CYPs including CYP1A1, CYP1A2, and CYP3A4, S-warfarin is primarily

Mephenytoin is a hydantoin-derivative anticonvulsant agent that is typically used to treat partial seizures in patients resistant to less-toxic drugs. It is supplied as a racemic mixture of the enantiomers R-mephenytoin and S-mephenytoin. Similar to warfarin, mephenytoin is subject to stereoselective metabolism, with S-mephenytoin being hydroxylated to 4-hydroxymephenytoin by CYP2C19, whereas R-mephenytoin is slowly demethylated. Accordingly, mephenytoin has been used as an in vivo probe of CYP2C19 activity by measuring the formation clearance of the CYP2C19 specific metabolite 4-hydroxymephenytoin. Mephenytoin was administered as a single oral dose to patients with varying degrees of CKD and pharmacokinetic parameters assessed.52

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No difference in the area under the curve of Smephenytoin or the formation clearance of the 4-hydroxymephenytoin metabolite suggests that CYP2C19 activity is not different in patients with CKD.

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reported in CKD studies.59 This work demonstrated a decrease in CYP2D6-mediated clearance and that drug clearance decreases as kidney disease progresses.

CYP2E1 CYP2D6 CYP2D6 is one of the most abundantly expressed hepatic cytochrome P450 enzymes. It metabolizes approximately 20% of the most commonly prescribed medications.13 The CYP2D6 gene is highly polymorphic, and many genetic variations (e.g. single nucleotide polymorphisms, gene insertions, gene deletions) are known to affect metabolism. However, discrepant findings pertaining to the effect of CKD on CYP2D6-mediated metabolism have been reported. Sparteine is a sodiumchannel blocker and class 1a antiarrhythmic agent used as an in vivo probe of CYP2D6. It is metabolized by CYP2D6 into the metabolites 2-dehydrosparteine and 5-dehydrosparteine. Dextromethorphan is a widely used antitussive agent that has also been used as an in vivo probe of CYP2D6. It is metabolized by CYP2D6 into dextrorphan, an active metabolite. CYP2D6 activity was assessed in 12 CKD patients and 12 healthy controls by administering 100 mg of sparteine and 40 mg of dextromethorphan on separate days. The initial interpretation of the study suggested that CYP2D6 activity was not altered by kidney disease.53 These data were subsequently reanalyzed using kinetic modeling, and the authors found that CYP2D6 activity was decreased in CKD.54 There is other support for decreased CYP2D6 in kidney disease. Other studies evaluating the effect of kidney disease have assessed the pharmacokinetics of metoprolol and paroxetine, both drugs that are highly metabolized by CYP2D6.55e57 These studies also show an increasing trend in plasma area under the curve, suggesting CYP2D6 activity is decreased. A more recent study investigated the effect of CKD and HD on nebivolol pharmacokinetics.58 Nebivolol is a beta blocker supplied as a racemic mixture of the enantiomers d-nebivolol and l-nebivolol and is metabolized by CYP2D6-mediated hydroxylation and glucuronidation. The area under the curve of both nebivolol enantiomers is increased in CKD patients compared to controls, and this is accompanied by a decrease in the CL/F.58 Interestingly, ESRD patients treated with HD have no change in AUC or CL/F compared to controls. Collectively, these data suggest that CYP2D6 activity is decreased in CKD and that HD restores CYP2D6 activity, potentially by removing uremic inhibitors of metabolism. The most convincing evidence of altered CYP2D6mediated metabolism in CKD is from an FDA analysis that systematically and quantitatively evaluated the pharmacokinetics of numerous CYP2D6 substrates

CYP2E1 metabolizes less than 5% of the most highly prescribed drugs13 but plays an important role in determining drug toxicity. Chlorzoxazone is a centrally acting muscle relaxant with sedative properties and is hydroxylated by CYP2E1 to form 6-hydroxychlorzoxazone. The formation clearance of 6-hydroxychlorzoxazone is commonly used as a marker of CYP2E1 metabolic activity. Chlorzoxazone was administered to patients with varying levels of kidney function to assess CYP2E1 activity.60 There was no difference in 6-hydroxychlorzoxazone formation clearance between patients, indicating that CYP2E1 activity is not affected by CKD.

CYP3A4 CYP3A4, the most abundantly expressed human CYP, metabolizes between 30% and 50% of marketed drugs.61 Similar to CYP2D6, the effect of CKD on CYP3A4 expression and activity is unclear. Although there are many preclinical studies that demonstrate CYP3A expression and activity are decreased in experimental models of CKD, the results of clinical pharmacokinetic studies in humans are less clear and highly variable. The macrolide antibiotic drug erythromycin has been used extensively as a probe substrate to evaluate CYP3A4 activity in vivo. The erythromycin breath test was developed to facilitate a relatively noninvasive method to probe CYP3A4 activity in patients. In the erythromycin breath test, patients are given 14 C-erythromycin, which is demethylated by CYP3A4. The demethylated carbon then appears in the breath as 14 CO2, which was presumed to be a surrogate of CYP3A4 activity. Decreased 14CO2 excretion in breath was interpreted as a decrease in CYP3A4 and conversely, increased breath 14CO2 was interpreted as increased CYP3A4 activity. Multiple studies used this approach to study CYP3A4 activity in CKD patients.62,63 14 CO2 excretion was decreased by 28% in ESRD patients compared to controls, suggesting CYP3A4 activity is decreased in this population.62 Interestingly, 14CO2 excretion is increased by 27% immediately following HD, suggesting that HD acutely restores CYP3A4 activity.63 Oral and intravenous pharmacokinetics of erythromycin was simultaneously assessed in control and ESRD patients. ESRD patients exhibited decreased hepatic clearance of erythromycin.64 Collectively, findings of these studies were interpreted on the basis of

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CYP3A4 alone, and all studies reported decreased CYP3A4 activity in kidney disease, based on the premise that erythromycin clearance is primarily mediated by CYP3A4.62e64 It is now known that erythromycin is not a specific probe of CYP3A4. In fact, the drug exhibits overlapping substrate specificity, as it is a substrate of CYP3A4 as well as organic anion transporting polypeptides (OATPs) and P-glycoprotein (P-gp) transporters.65,66 Therefore, although erythromycin pharmacokinetics is altered in CKD, it is unlikely to be due exclusively to altered CYP3A4-mediated metabolism. Another widely used in vivo probe of CYP3A4 activity is the short-acting benzodiazepine midazolam. In contrast to erythromycin, midazolam is not a substrate for any uptake (e.g. OATP) or efflux (e.g. P-gp, BCRP) transporters. Plasma concentration time curves of midazolam and the CYP3A4-mediated metabolite 1-OH midazolam are nearly superimposable in ESRD and control patients after oral administration, with no differences in AUC or CL/F, suggesting that CYP3A4 is not altered in kidney disease.67 However, in contrast to oral midazolam, ESRD patients treated with HD who received IV midazolam had a fivefold increase in AUC and a 65% decrease in clearance compared to control.68 This difference was not observed in ESRD patients treated with peritoneal dialysis (PD). Although this study demonstrates decreased clearance of midazolam and suggests that hepatic CYP3A4 activity is decreased in CKD, it is surprising that midazolam half-life was not different between ESRD and control patients. The complexity of the impact of CKD on nonrenal clearance has been highlighted by FDA investigators who assessed the impact of CKD on the systemic exposure of several new drugs.69 Some CYP3A4 substrates required dosage adjustment in CKD while others did not.69 For example, tadalafil is extensively metabolized by CYP3A4 and minimally eliminated by the kidney (fractional excretion <0.3%). ESRD patients taking tadalafil have a twofold increase in the maximal plasma concentration and a 2.7e4.1-fold increase in the AUC compared to controls. Accordingly, a reduction in dose is recommended for ESRD patients.69 Solifenacin has a fractional excretion of 15% and is extensively metabolized by CYP3A4. In CKD, solifenacin maximal plasma concentration, AUC, and half-life are increased by 1.2-, 2.1-, and 1.6-fold, respectively, and dose reduction is recommended in CKD.69 Conversely, alfuzosin and vardenafil are CYP3A4 substrates and are minimally excreted in the urine but demonstrate only modest increases in maximal plasma concentration and AUC. There are no recommendations for altered dosing for alfuzosin and vardenafil in CKD.69 Further analysis of 18 different CYP3A4/5 model drugs in 24 different studies to evaluate the systemic and quantitative effect of CKD on CYP3A4/5 provided additional insight.59 Although

CYP2D6 model drugs demonstrate a consistent decrease in clearance in CKD patients, CYP3A4/5 model drugs exhibit variable responses, with no clear relationship between kidney function and changes in drug clearance. For the CYP3A4/5 model drugs that exhibited decreased clearance, the magnitude of change was modest. Collectively, clinical pharmacokinetic studies in humans suggest that CYP3A4/5 may be modestly decreased or not changed in CKD patients. There does not appear to be consistency among model drug substrates, which likely points to some nonspecificity of probes (e.g. substrate of multiple CYPs or transporters) and the relatively minimal impact of CKD on hepatic CYP3A4.

Hepatic Reductases Multiple drugs that undergo hepatic reduction exhibit altered pharmacokinetics in patients with kidney disease, suggesting that this pathway of nonrenal clearance involved. Two of the best-studied examples include the anthracyclines doxorubicin and idarubicin, which undergo hepatic reduction to doxorubicinol and idarubicinol, respectively. Following a 40e60 mg IV infusion of doxorubicin, HD patients had a 71% increase in AUC and a corresponding 41% decrease in total clearance compared to controls with normal kidney function.70 The altered doxorubicin clearance was a result of decreased doxorubicinol formation. Doxorubicin is metabolized by the hepatic reductases CBR1 and AKR1C3, so the altered pharmacokinetics is likely a result of decreased activity of these hepatic reductases. Idarubicin pharmacokinetics was studied in patients with impaired kidney function following a single 12 mg/m2 dose.71 Patients with a creatinine clearance less than 60 mL/min had a 38% increase in idarubicin AUC and a 30% decrease in total clearance. Ex vivo studies using cytosolic and microsomal fractions from cadaveric liver samples obtained from ESRD and control patients have investigated the effect of CKD on hepatic reductase expression and activity.72 Western blotting demonstrated a 65% decreased protein expression of carbonyl reductase 1 in CKD livers, and a trend toward decreased mRNA expression was observed. These data may partially explain the altered pharmacokinetics of substrate drugs such as warfarin, doxorubicin, and idarubicin in CKD patients.

NAT2 Although less commonly studied, there is evidence for altered phase II drug-metabolizing enzymes such as NAT2 in patients with kidney disease. The

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prototypical probe drug for NAT2 activity in vivo is isoniazid, an antibacterial agent used to treat tuberculosis. Isoniazid is most commonly used to classify patients as rapid or slow acetylators based on their NAT2 genotype. NAT2 activity was determined in rapid and slow acetylator ESRD patients prior to and following kidney transplantation.73 The nonrenal clearance of isoniazid improved by over 50% in rapid acetylators and 225% in slow acetylators following kidney transplantation. This suggests that NAT2 activity is decreased in kidney disease and that restoration of kidney function by transplantation improves NAT2 activity. A similar finding of decreased NAT2-mediated activity was found in CKD patients using the NAT substrate procainamide.74

UGTs Morphine and other opioid analgesics undergo extensive glucuronidation with some of the resultant glucuronide metabolites lacking pharmacological activity (e.g. morphine 3-glucuronide), whereas others are pharmacologically active (e.g. morphine 6-glucuronide). Morphine pharmacokinetics are substantially altered in patients with CKD, as they have a significantly increased AUC and decreased clearance following standard dosing, compared to control subjects with normal kidney function.75 Morphine is metabolized by UGT1A3 and UGT2B7. The increased AUC and decreased clearance suggest the activity of these enzymes may be impaired in CKD. Other drugs that are extensively metabolized via glucuronidation such as the NSAID diacerein76 and the nucleoside reverse transcriptase inhibitor zidovudine77 exhibit decreased nonrenal clearance in patients with CKD, supporting a decrease in UGT-mediated metabolism in kidney disease.

DRUG TRANSPORT IN PRECLINICAL MODELS OF CKD Although the impact of drug metabolism to overall drug disposition has been known for decades, it was only recently that the importance of drug transporters to drug disposition and pharmacokinetics has been appreciated. Accordingly, our understanding of the impact of CKD on drug transporters has lagged behind that of drug-metabolizing enzymes. The subtotal 5/6 nephrectomy used to study the impact of CKD on drug metabolism has also been employed to study drug transporters. Starting in the late 2000s, Naud, Leblond, Pichette, and colleagues used the 5/6 nephrectomy model to study the impact of CKD on transporter expression and activity.45,78e80

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At the level of the intestine, transporters play an essential role in determining the oral bioavailability of substrate drugs, with uptake transporters enhancing oral bioavailability and efflux transporters restricting drug absorption (Figure 63.3). Rats with experimental CKD (5/6 nephrectomy) had 65%, 60%, and 35% reductions in the intestinal protein expression of the efflux transporters P-gp, multidrug resistanceeassociated protein 2 (MRP2), and MRP3, respectively.79 Surprisingly, the mRNA expression of these transporters was not different between CKD and control animals. Transport activity of P-gp and MRP2 transporters were assessed using everted gut sacs and the probe substrates rhodamine 123 for P-gp and 5-(and 6-) carboxy 20 ,70 dichlorofluorescein for MRP2. CKD rats had a 30% reduction in P-gp activity and a 23% reduction in MRP2 activity compared to control. There were no significant differences in the expression of the uptake transporters Oatp2 or Oatp3. An additional study evaluated the effect of CKD in rats subjected to 5/6 nephrectomy. The investigators found no change in the mRNA expression of intestinal efflux transporters, but they were unable to assess protein expression or activity.81 The likely implications of downregulated protein expression of P-gp, MRP2, and MRP3 in the setting of CKD is an increased bioavailability of substrate drugs. Hepatic uptake and efflux transporters have also been evaluated in rats with CKD and sham control animals.80 Protein expression of the uptake transporter Oatp2 was downregulated by 35% in CKD animals compared to control with no change in the mRNA expression. In contrast to intestinal efflux transporters, hepatic P-gp protein and mRNA expression were upregulated by 25% and 50%, respectively. Injection of the P-gp probe rhodamine 123 revealed an approximately 50% increased biliary clearance, which supports a functional increase in hepatic P-gp activity in CKD. Although surprising that CKD appears to cause opposite effects in terms of P-gp activity in intestine compared to liver, a recent study has shed light on these seemingly contrasting findings. Using a human hepatoma cell line (HepG2) and both the adenine and 5/6 nephrectomy models of CKD in mice, Machado and colleagues demonstrated that the uremic toxin indoxyl sulfate upregulates P-gp in the liver by acting as a ligand for the aryl hydrocarbon receptor (AhR).82 Indoxyl sulfate is a gut-derived uremic toxin made from indole synthesized from gut bacteria. Although indole is made in the gut, it is oxidized and sulfated in the liver, potentially explaining hepatic P-gp specific upregulation. Further studies have evaluated the effect of 5/6 nephrectomy in rats on kidney and brain transporters. Transporters expressed on the apical and basolateral membranes of kidney tubule cells have a profound impact on the secretion and reabsorption of drugs

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FIGURE 63.3 Intestinal drug metabolism and transport pathways. The majority of orally administered drugs are absorbed in the proximal intestine (duodenum and jejunum). These intestinal regions contain microvilli that increase the surface area for absorption. The apical membrane of intestinal enterocytes face the lumen of the intestine and have high expression of both uptake (blue spheres) and efflux (purple spheres) transporters. Enterocytes also express phase I and II drug-metabolizing enzymes and transporters on the basolateral membrane. Representative transporters and enzymes are shown for reference, note this is not a complete list. Images used to generate this figure were modified from Servier Medical Art, licensed under Creative Commons Attribution 3.0 Generic License, http://smart.servier.com/.

(Figure 63.4). In CKD rats the protein expression of several uptake transporters is downregulated, including organic anion transporter 1 (Oat1), Oat2, Oat3, organic anion transporting polypeptide (Oatp) 1, and Oatp4c1.45 In contrast, Oatp2 and Oatp3 have increased protein expression in CKD. Efflux transporters Mrp2, Mrp3, and Mrp4 have increased protein expression in CKD. P-gp protein expression is downregulated in CKD kidneys. To assess the functional implication of CKD on transporter activity, 14C-benzylpenicillin was used as a probe of Oat and Mrp transporters and 3H-digoxin was used as a probe of Oatp4c1 and P-gp. The kidney/plasma ratio of 14C-benzylpenicillin and 3 H-digoxin were increased nine-fold and four-fold, respectively, in CKD animals compared to control animals. These data suggest that CKD causes a reduction in transporter-mediated drug elimination and renal drug accumulation, which could further exacerbate kidney damage. Endothelial cells at the bloodebrain barrier help restrict drug entry into the brain. In CKD rats the protein expression of many bloodebrain barrier transporters is reduced, including breast cancer resistance protein (Abcg2), Mrp2, Mrp4, P-gp, Oat3, Oatp2, and Oatp3.78 14 C-Benzylpenicillin, 3H-digoxin, 14C-doxorubicin, and 3 H-verapamil were used to assess the impact of CKD on transporter function. Surprisingly, the brain to

plasma ratio was not different for 3H-digoxin, 14 C-doxorubicin, and 3H-verapamil, but it was decreased by 30% for 14C-benzylpenicillin. These data suggest that a large fraction of bloodebrain barrier integrity is preserved in CKD, despite significant reduction in the expression of many transporters.

DRUG TRANSPORT IN HUMANS WITH CKD Drug transport in CKD is studied using similar approaches to drug metabolism. The pharmacokinetics of substrate drugs are evaluated, in particular the AUC and nonrenal clearance. Recent evidence suggests that several drug transporter substrates have altered pharmacokinetics in patients with kidney disease. Delineating the specific drug transporters that are affected in CKD has been difficult as many of the commonly used probe drugs are substrates of multiple transporters, and some are also metabolized. The most consistent finding of altered drug transporter activity in vivo in CKD patients has been demonstrated using the transporter probe fexofenadine. Fexofenadine is useful for studying drug transporter activity in CKD because it is minimally metabolized and

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FIGURE 63.4 Kidney drug metabolism and transport pathways. The nephron is commonly thought of as the primary functional unit of the kidney. Although drug metabolism and transporter functions can be found at many regions of the nephron, the most commonly studied region are the proximal tubule cells. Uptake transporters (blue spheres) expressed on the basolateral membrane of proximal tubule cells carry drugs from the blood into the tubule cell. The tubule cells express several phase I (e.g. CYP) and phase II drug-metabolizing enzymes that may metabolize drugs. The apical membrane of proximal tubule cells expresses several efflux transporters (purple spheres) that move drugs from the tubule cell to the urinary filtrate in the lumen of the nephron to facilitate renal drug excretion. Although not shown here, there are also uptake transporters expressed at the apical membrane of proximal tubule cells that mediate drug uptake. Representative transporters and enzymes are shown for reference, note this is not a complete list. Images used to generate this figure were modified from Servier Medical Art, licensed under Creative Commons Attribution 3.0 Generic License, http://smart.servier.com/.

minimally excreted in the urine. Unfortunately, fexofenadine is transported by multiple uptake (e.g. OATP1B1, OATP1B3, OATP2B1) and efflux (P-gp, MRP2, MRP3) transporters, making the link between altered activity and an individual transporter very difficult to establish. Fexofenadine (120 mg oral dose) was administered to healthy controls and ESRD patients treated with maintenance HD.67 The ESRD patients had a 2.8-fold increase in the AUC and a 63% reduction in clearance. In a similar study design, patients with biopsy-proven glomerulonephritis (systemic lupus erythematosus nephritis or small vessel vasculitis) were given 60 mg of fexofenadine.83 The oral clearance of fexofenadine in glomerulonephritis patients was reduced by 40% compared to healthy controls. In a third study, patients with moderate to severe CKD (mean eGFR ¼ 17 mL/ min/1.73 m2) and patients with ESRD treated by HD and PD were given 120 mg of fexofenadine.68 The AUC in CKD, HD, and PD patients was increased by 2.9-, 2.3-, and 2.1-fold with a corresponding 61%, 56%, and 49% decrease in CL/F. Collectively, these three studies provide very strong evidence that transporter activity is altered in CKD. Similar to fexofenadine, the HMG CoA reductase inhibitor rosuvastatin is minimally excreted in the urine (fractional excretion less than 6%) and has negligible

hepatic metabolism. In addition, rosuvastatin is a substrate of multiple uptake (OATP1B1, OATP1B3, OATP2B1, OATP1A2, NTCP) and efflux (P-gp, BCRP, MRP2) transporters. Rosuvastatin plasma concentrations in patients with CKD (creatinine clearance less than 30 mL/min) are threefold higher than controls with normal kidney function, and steady state plasma concentrations are 50% higher in ESRD patients on maintenance HD.69 Recommendations suggest that the dose of rosuvastatin in kidney disease patients should be decreased (start at 5 mg and not exceed 10 mg). Although it is difficult to delineate the pathway responsible for the altered rosuvastatin pharmacokinetics, it appears likely that OATP transporter activity is decreased in CKD, resulting in an increased accumulation of the drug in the plasma. FDA investigators presented further evidence that OATP transporter function is impaired in humans with kidney disease84 by evaluating 20 CKD studies of 12 different OATP substrate drugs with a fractional excretion less than 33%. The drugs included atorvastatin, bosentan, cerivastatin, erythromycin, fluvastatin, imatinib, pitavastatin, repaglinide, rosuvastatin, and torsemide. The ratio of clearance in CKD patients (mild, moderate, severe, and ESRD) to clearance in healthy controls for both total (free þ protein bound) and free

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drug demonstrated a clear trend of decreasing OATP substrate clearance as kidney disease progresses. Although none of the drugs are “pure” OATP substrates (they all are substrates of other transporters and/or drug-metabolizing enzymes), this clear relationship over a large number of drugs strongly suggests OATP mediated clearance is decreased in kidney disease.

MECHANISMS OF ALTERED DRUG METABOLISM AND TRANSPORT IN CKD The mechanisms of altered drug metabolism and transport in CKD patients are somewhat controversial. Findings from preclinical models of CKD and human pharmacokinetic studies clearly indicate that kidney disease causes altered drug metabolism and transport in addition to the predictable decreases in renal excretion. The majority of reports suggest that molecules normally excreted by the functioning kidney, which are retained in CKD (uremic toxins), either 1) directly inhibit drug metabolizing enzymes and/or transporters or 2) cause up- or downregulation of expression through modification of transcriptional/translational processes. The uremic toxin hypothesis has been extensively reviewed.14

Direct Inhibition of Drug-Metabolizing Enzymes and Transporters The first mechanism hypothesized for altered drug metabolism and transport in CKD is that uremic mediators directly inhibit drug metabolizing enzymes and/or transporters. For example, when microsomes from nonCKD subjects were incubated with plasma from ESRD patients, CYP2C9-mediated tolbutamide metabolism decreased by 37% and CYP3A4 midazolam metabolism decreased by 80%.85 Altered erythromycin pharmacokinetics have been observed in multiple human studies, and it is now well appreciated that erythromycin is a substrate of several transporters and the drug-metabolizing enzyme CYP3A4.62,64,67 The effect of uremic toxins on erythromycin transport and metabolism was evaluated using rat hepatocytes and microsomes.86 After incubation of multiple uremic toxins, 3-carboxy-4-methyl-5-propyl-2furan-propanoic acid (CMPF) was demonstrated to inhibit the OATP-mediated uptake of erythromycin into hepatocytes, whereas indoxyl sulfate was shown to inhibit its CYP3A-mediated metabolism. Further evidence for the direct inhibition hypothesis comes from a human study evaluating erythromycin disposition before and after HD.63 An improvement in erythromycin disposition (i.e. improved metabolism and/or transport) following HD was determined using the

erythromycin breath test. As this was an acute study, it is likely that dialyzable uremic toxins removed during HD mediated this increase in metabolism and/or transport. The effect of uremic toxins on OATP-mediated transport was further studied by transfecting human embryonic kidney cells (HEK293) with OATP1B1, OATP1B3, and OATP2B1.87 The cells were then incubated with various uremic toxins and the cellular uptake of the OATP probe 3H-estrone sulfate was evaluated. Uremic toxins had a profound effect on OATP-mediated transport. OATP1B1 was inhibited by indoxyl sulfate, CMPF, endothelin, quinolinic acid, indole-3-acetic acid, p-cresol, and homocysteine, whereas OATP1B3 was inhibited by indoxyl sulfate, CMPF, and p-cresol. Finally, OATP2B1 was inhibited only by CMPF. It should be noted that p-cresol is sometimes indirectly quantified as a by-product of p-cresyl sulfate, which is now known to be the circulating uremic toxin found in patients with kidney disease.

Altered Expression of Drug-Metabolizing Enzymes and Transporters Although human pharmacokinetic studies make it difficult to determine altered expression of drug metabolism and transport in CKD, animal studies and experiments using in vitro cell culture techniques make it possible to interrogate mechanisms. Studies in animal models of CKD consistently demonstrate that CKD causes a decrease in enzyme and transporter mRNA and protein expression, which strongly suggests a transcriptional/translational mechanism. Several studies have taken these observations further in an attempt to delineate the mechanism. Using the 5/6 nephrectomy, chromatin immunoprecipitation (ChIP) was performed to evaluate transcription factor binding to the promoter region of the Cyp2c11 and Cyp3a2 genes in control and CKD rats.88 Binding of RNA polymerase II to the Cyp2c11 and Cyp3a2 promoters was significantly decreased in CKD compared to controls, confirming that downregulation of these enzymes in preclinical models is mediated by decreased transcription. Further analysis demonstrated that the binding of transcription factors PXR and HNF4a to the promoter of Cyp2c11 (HNF4a) and Cyp3a2 (PXR and HNF4a) are decreased in CKD compared to controls. These nuclear receptors are primary determinants of CYP expression. The studies also indicated that CKD was associated with decreased histone acetylation, suggesting CKD induces epigenetic changes that may mediate altered expression. Parathyroid hormone (PTH) has been proposed to be a uremic toxin that mediates the decreased expression of hepatic Cyp3a in rats with CKD. Studies that incubated

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REFERENCES

rat hepatocytes with human serum from CKD patients and healthy controls demonstrated that CKD serum downregulated the expression and activity of Cyp3a. When serum was fractionated, it was the fraction with a molecular weight between 10e15 kDa that mediated this decrease.37 In a follow-up study, parathyroidectomy was shown to reverse the CKD-mediated decrease in Cyp3a expression and activity. Incubation with PTH dose dependently decreased Cyp3a expression in cultured rat hepatocytes.36 Uremic mediators that downregulate CYP expression and activity appear to be dialyzable.35 Rat hepatocytes incubated with serum obtained predialysis caused a 27% and 35% decrease in Cyp2c and Cyp3a protein expression, respectively. Serum obtained postdialysis had no effect on CYP expression.

OTHER CONSIDERATIONS IN KIDNEY DISEASE PATIENTS Although alterations in drug metabolism and transport must be considered when prescribing drugs to patients with kidney disease, renal replacement therapy adds further complexity. The impact of dialytic clearance on plasma concentrations and, consequently, renal drug dosing must be considered. Dialytic clearance can be substantially different from renal clearance and is predominantly determined by the molecular weight, volume of distribution and protein binding of the drug, the type of dialysis membrane, and blood/dialysate flow rates.21 There is a paucity of information currently, with data on drug dialyzability with measured clearance available for only about 10% of marketed drugs.21 In addition, much of the information available is determined using the suboptimal arterialvenous (AV) difference method, which is known to overestimate clearance.89 Treating physicians can often select multiple drugs within the same class, and little information is available to determine which drug is most suitable in dialysis patients. Significant differences in drug dialyzability may exist, even among drugs within the same class.12 For instance, atenolol and metoprolol are extensively cleared during HD, bisoprolol is moderately cleared, and the clearance of carvedilol is negligible.12

SUMMARY Patients with kidney disease are prescribed numerous medications and commonly receive treatment with drugs that are predominantly cleared by nonrenal pathways. The nonrenal clearance of many drugs is

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altered in patients with impaired kidney function, often translating into clinically relevant changes in systemic exposure (see Table 63.1). This in turn may change the efficacy and adverse effect profile in patients if the drug dose is not adjusted. Although the precise mechanism of changes in nonrenal clearance pathways is unclear, selective modulation of activity and expression of drug-metabolizing enzymes and transport proteins has been implicated. Transcriptional, translational, and posttranslational modification, perhaps induced by uremic toxins, may play a role. Clinicians are encouraged to consider the impact of kidney disease on all aspects of safety and efficacy during the drug selection process. Although these data are limited currently, the US FDA now recommends that clinical studies be conducted for investigational compounds eliminated primarily via nonrenal pathways as well as those eliminated predominantly unchanged in the urine. Eventually this will generate improved data related to the impact of kidney disease on drug dosing requirements and will improve efficacy and safety in one of the most vulnerable patient populations.

References 1. USRDS. Available from: https://www.usrds.org/adrhighlights. aspx. 2. Coresh J, et al. Prevalence of chronic kidney disease in the United States. J Am Med Assoc 2007;298(17):2038e47. 3. Gansevoort RT, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382(9889):339e52. 4. Spence JD, Urquhart BL, Bang H. Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine. Nephrol Dial Transplant 2016;31(6):937e44. 5. Stubbs JR, et al. Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden. J Am Soc Nephrol 2016;27(1):305e13. 6. Bogiatzi C, et al. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis 2018;273:91e7. 7. Chiu YW, et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 2009;4(6):1089e96. 8. Manley HJ, et al. Medication prescribing patterns in ambulatory haemodialysis patients: comparisons of USRDS to a large not-forprofit dialysis provider. Nephrol Dial Transplant 2004;19(7):1842e8. 9. Manley HJ, et al. Medication-related problems in ambulatory hemodialysis patients: a pooled analysis. Am J Kidney Dis 2005; 46(4):669e80. 10. Farag A, et al. Dosing errors in prescribed antibiotics for older persons with CKD: a retrospective time series analysis. Am J Kidney Dis 2014;63(3):422e8. 11. FDA. Pharmacokinetics in patients with impaired renal function d study design, data analysis, and impact on dosing and labeling. 2010. Available from: http://www.fda.gov/downloads/Drugs/.../ Guidances/UCM204959.pdf. 12. Tieu A, et al. Beta-blocker dialyzability in maintenance hemodialysis patients: a randomized clinical trial. Clin J Am Soc Nephrol 2018;13(4):604e11.

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37. Michaud J, et al. Effects of serum from patients with chronic renal failure on rat hepatic cytochrome P450. Br J Pharmacol 2005;144(8): 1067e77. 38. Guevin C, et al. Down-regulation of hepatic cytochrome p450 in chronic renal failure: role of uremic mediators. Br J Pharmacol 2002;137(7):1039e46. 39. Leblond F, et al. Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 2001;12(2):326e32. 40. Leblond FA, et al. Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos 2000;28(11):1317e20. 41. Velenosi TJ, et al. Down-regulation of hepatic CYP3A and CYP2C mediated metabolism in rats with moderate chronic kidney disease. Drug Metab Dispos 2012;40(8):1508e14. 42. Terai K, Mizukami K, Okada M. Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphataemia model. Nephrology 2008;13(2):139e46. 43. Feere DA, Velenosi TJ, Urquhart BL. Effect of erythropoietin on hepatic cytochrome P450 expression and function in an adenine-fed rat model of chronic kidney disease. Br J Pharmacol 2015;172(1): 201e13. 44. Leblond FA, et al. Downregulation of intestinal cytochrome p450 in chronic renal failure. J Am Soc Nephrol 2002;13(6):1579e85. 45. Naud J, et al. Effects of chronic renal failure on kidney drug transporters and cytochrome P450 in rats. Drug Metab Dispos 2011;39(8): 1363e9. 46. Alshogran OY, et al. Effect of experimental kidney disease on the functional expression of hepatic reductases. Drug Metab Dispos 2015;43(1):100e6. 47. Yu C, et al. Effect of chronic renal insufficiency on hepatic and renal udp-glucuronyltransferases in rats. Drug Metab Dispos 2006;34(4): 621e7. 48. Simard E, et al. Downregulation of hepatic acetylation of drugs in chronic renal failure. J Am Soc Nephrol 2008;19(7):1352e9. 49. Turpeinen M, et al. Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites. Br J Clin Pharmacol 2007; 64(2):165e73. 50. Joy MS, et al. Use of enantiomeric bupropion and hydroxybupropion to assess CYP2B6 activity in glomerular kidney diseases. J Clin Pharmacol 2010;50(6):714e20. 51. Dreisbach AW, et al. Cytochrome P4502C9 activity in end-stage renal disease. Clin Pharmacol Ther 2003;73(5):475e7. 52. Nolin TD, et al. Effect of chronic kidney disease on cytochrome P450 2C19 activity and 4-hydroxymephenytoin urinary recovery. Clin Pharmacol Ther 2007;81(Suppl. 1):S56. 53. Kevorkian JP, et al. Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan. Clin Pharmacol Ther 1996;59(5):583e92. 54. Rostami-Hodjegan A, Kroemer HK, Tucker GT. In-vivo indices of enzyme activity: the effect of renal impairment on the assessment of CYP2D6 activity. Pharmacogenetics 1999;9(3):277e86. 55. Kaye CM, et al. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand Suppl 1989;350:60e75. 56. Hoffmann KJ, et al. The effect of impaired renal function on the plasma concentration and urinary excretion of metoprolol metabolites. Clin Pharmacokinet 1980;5(2):181e91. 57. Jordo L, et al. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmacokinet 1980;5(2):169e80. 58. Neves DV, et al. Influence of chronic kidney disease and haemodialysis treatment on pharmacokinetics of nebivolol enantiomers. Br J Clin Pharmacol 2016;82(1):83e91. 59. Yoshida K, et al. Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5. Clin Pharmacol Ther 2016;100(1):75e87.

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76. Debord P, et al. Influence of renal function on the pharmacokinetics of diacerein after a single oral dose. Eur J Drug Metab Pharmacokinet 1994;19(1):13e9. 77. Singlas E, et al. Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis. Clin Pharmacol Ther 1989;46(2):190e7. 78. Naud J, et al. Effects of chronic renal failure on brain drug transporters in rats. Drug Metab Dispos 2012;40(1):39e46. 79. Naud J, et al. Down-regulation of intestinal drug transporters in chronic renal failure in rats. J Pharmacol Exp Ther 2007;320(3): 978e85. 80. Naud J, et al. Effects of chronic renal failure on liver drug transporters. Drug Metab Dispos 2008;36(1):124e8. 81. Lu H, Klaassen C. Gender differences in mRNA expression of ATPbinding cassette efflux and bile acid transporters in kidney, liver, and intestine of 5/6 nephrectomized rats. Drug Metab Dispos 2008;36(1):16e23. 82. Santana Machado T, et al. Indoxyl sulfate upregulates liver Pglycoprotein expression and activity through aryl hydrocarbon receptor signaling. J Am Soc Nephrol 2018;29(3):906e18. 83. Joy MS, et al. In vivo alterations in drug metabolism and transport pathways in patients with chronic kidney diseases. Pharmacotherapy 2014;34(2):114e22. 84. Tan ML, et al. Effect of chronic kidney disease on nonrenal elimination pathways: a systematic assessment of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP. Clin Pharmacol Ther 2018;103(5): 854e67. 85. Taburet AM, et al. Impairment of drug biotransformation in renal disease: an in vitro model. Clin Pharmacol Ther 1996;59: 136. 86. Sun H, et al. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos 2004;32(11): 1239e46. 87. Reyes M, Benet LZ. Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics. J Pharm Sci 2011;100(9):3831e42. 88. Velenosi TJ, et al. Decreased nuclear receptor activity and epigenetic modulation associates with down-regulation of hepatic drug-metabolizing enzymes in chronic kidney disease. FASEB J 2014;28(12):5388e97. 89. Tieu A, et al. Clearance of cardiovascular medications during hemodialysis. Curr Opin Nephrol Hypertens 2016;25(3):257e67. 90. Nolin TD. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens 2008;17(6):555e9.

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QUESTIONS AND ANSWERS Question 1 A new drug for the treatment of hypertension is being tested in patients with CKD. It is an OATP1B1 substrate and has a fractional excretion <5%. Which of the following pharmacokinetic changes are most likely to be observed in a CKD patient compared to a control? A. B. C. D. E.

An increase in the AUC and CL/F A decrease in the AUC and CL/F An increase in the AUC and a decrease in the CL/F A decrease in the AUC and an increase in the CL/F An increase in the AUC and a decrease in the half-life

Answer: C Hepatic OATP function is decreased in CKD. The result of decreased OATP activity is a decrease uptake of the drug into the liver, which will result in an increase in the AUC. As the drug has a very low fractional excretion, its excretion is mediated by nonrenal clearance mechanisms. The decreased OATP function will in turn result in a decrease oral clearance (CL/F) as CL/ F ¼ dose*F/AUC.

Question 2 Morphine is administered to a patient with CKD with no consideration of the impact of the patient’s decreased kidney function. Which of the following is the most likely outcome? A. The patient may experience an increased analgesic response to morphine and may also experience respiratory depression B. The patient may have a blunted analgesic response to morphine C. The plasma levels and AUC for morphine may be decreased compared to a patient with normal kidney function D. The patient may need more frequent administration of morphine for analgesia E. Increased drug transporter expression at the bloodebrain barrier may restrict the entry of morphine to the brain, decreasing the analgesic response. Answer: A Morphine is cleared primarily by glucuronidation with a small fraction cleared unchanged in the urine. Morphine pharmacokinetics are substantially altered in kidney disease with an increased AUC and decreased CL. In addition, some morphine metabolites (e.g. morphine 6-glucuronide) have activity at opioid receptors and are renally cleared. A CKD patient that receives morphine without careful consideration of disease stage

may have increased therapeutic response (analgesia) but may also be susceptible to side effects such as respiratory depression.

Question 3 Which of following statements most accurately reflects CYP3A4 activity in CKD? A. CYP3A4 activity is markedly reduced in CKD B. CYP3A4 activity is significantly increased in CKD C. Increased erythromycin AUC and decreased CL/F in CKD patients indicates decreased CYP3A4 activity D. Only select CYP3A4 substrates exhibit decreased clearance in CKD and the magnitude of change is modest E. Vardenafil AUC is substantially increased in CKD and dose adjustment is required Answer: D Although studies in preclinical animal models of CKD consistently demonstrate decreased activity, clinical pharmacokinetic studies are much more variable. Although CYP3A4 substrates such as erythromycin have an increased AUC and decreased CL/F, it is unclear what role changes in drug transporter activity have on mediating the decreased clearance. The best currently available evidence suggests that only some CYP3A4 substrates have decreased clearance in CKD and the magnitude of decrease for these substrates is only modest.

Question 4 Which of the following best describes the impact of CKD on P-gp expression and activity using preclinical models? A. Intestinal and hepatic P-gp expression and activity are increased B. Intestinal and hepatic P-gp expression and activity are decreased C. Intestinal P-gp expression and activity are decreased whereas hepatic P-gp expression and activity are increased D. Intestinal P-gp expression and activity are increased whereas hepatic P-gp expression and activity are decreased E. There is no change of intestinal or hepatic P-gp expression and activity in CKD Answer: C Intestinal P-gp expression is decreased in preclinical models of CKD. Studies demonstrate that this decreased expression results in a decrease in substrate (rhodamine 123) transport. Conversely, hepatic P-gp expression is

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QUESTIONS AND ANSWERS

increased in preclinical models of CKD. These animals have increased biliary clearance of the P-gp substrate rhodamine 123. The opposite effects in intestine and liver may be mediated by the uremic toxin and AhR ligand indoxyl sulfate. Indoxyl sulfate is generated in the liver from indole. Accordingly, intestinal exposure is expected to be minimal in relation to hepatic.

Question 5 Substrates of which CYP enzyme most consistently exhibit decreased clearance as kidney disease progresses? A. B. C. D. E.

CYP2C19 CYP2D6 CYP2E1 CYP3A4 CYP1A2

Answer: B Clearance of CYP1A2, CYP2C19, and CYP2E1 substrates do not appear to be decreased in CKD. Although some CYP3A4 substrates exhibit decreased clearance, others do not. There is no clear relationship between clearance and kidney disease stage. The CYP enzyme

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that most consistently exhibits decreased clearance is CYP2D6. In addition, there is a clear relationship between kidney disease stage and clearance for multiple CYP2D6 substrate drugs.

Question 6 Which of the following best explains the increased AUC and decreased CL of doxorubicin in patients with CKD? A. B. C. D. E.

Decreased CYP2D6-mediated metabolism in CKD Decreased NAT2 activity in CKD Decreased UGT2B7 activity in CKD Decreased CYP3A4 activity in CKD Decreased CBR1 activity in CKD

Answer: E Doxorubicin does not undergo substantial metabolism by any CYP enzymes. Hepatic reduction by CBR1 and AKR1C3 are the primary metabolic pathways responsible for reducing doxorubicin into doxorubicinol. CBR1 expression is decreased in CKD, and this most likely causes the increased AUC and decreased clearance observed in patients.

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