- Email: [email protected]
Med-Psych Drug-Drug Interactions Update
Med-Psych Drug-Drug Interactions Update Scott C. Armstrong, M.D., Kelly L. Cozza, M.D., Jessica R. Oesterheld, M.D. (Guest Contributor)
W
e review three topics in this edition of Med-Psych DDI Update. First, we have a guest reviewer, Dr. Jessica R. Oesterheld, who informs us of a class of metabolic enzymes—the uridine diphosphate glucuronosyl transferases (UGTs). These enzymes are becoming more important to appreciate in terms of potential drug-drug interaction (DDI). We then review the cholinesterase inhibitors, the only drugs approved for treatment of Alzheimer’s dementia, and the hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, or ‘‘statin’’ drugs, which are used to aid in lowering cholesterol.
1. UGTs and Drug Interactions The hepatic P450 cytochromes have been center stage as the major culprits of most pharmacokinetic drug-drug interactions. Another superfamily of enzymes, the uridine diphosphate glucuronosyl transferases (UGTs) are beginning to emerge as challenging. Because it was only in 1997 that a UGT nomenclature was developed, data
TABLE 1. UGT
about them are at the stage that P450 cytochromes facts were about 10 years ago. Psychiatrists should know the basics about UGTs because some important medical and psychiatric drugs use these pathways, and they may interact with each other. P450 cytochromes begin the process of metabolism of lipid-soluble drugs to increasingly water-soluble metabolites so that drugs can be inactivated and excreted in the bile or urine. P450 cytochromes (Phase 1) break off part of the drug and insert or uncover a molecule (usually oxygen) to expose ‘‘a handle’’ so that conjugating enzymes (Phase 2) can form a link to that handle via a transferring enzyme. The most abundant conjugate is a sugar, glucuronic acid, and the UGTs are found close to the P450 cytochromes in the endoplasmic reticulum. Many important endogenous substrates such as bilirubin, bile acids, and most steroids are substrates of UGTs, as are more than 350 exogenous compounds. Drugs commonly encountered by psychiatrists who work in medical-surgical settings that are primarily handled by the UGTs include lamotrigine, valproate, nonsteroidal anti-inflammatory drugs, 3⬘-azido-3⬘-deoxythimidine (AZT), and morphine (see Table 1).
Most drugs are metabolized via both Phase 1 and Phase 2 processes, but some drugs that already have a ‘‘handle’’ are directly conjugated by UGTs. Psychiatrists are already aware that most benzodiazepines are first metabolized by the P450 system and then glucuronidated. Lorazepam, oxazepam, and temazepam are directly glucuronidated, making them the preferential benzodiazepines to be used in patients with hepatic disease because UGTs are less affected than P450s. Most glucuronidated drugs are inactive, but there are notable exceptions (e.g., morphine-6-glucuronate is 50 times more potent than morphine). UGTs are also found throughout the gastrointestinal tract, kidney, and brain and elsewhere in the body. UGT amino acids have been sequenced, and a nomenclature has been developed based on amino acid similarity. The website for the committee responsible for naming UGTs is located at http://www.unisa.edu.au/pharm_medsci /Gluc_trans/default.htm. Identical to the nomenclature of the P450s, the root symbol is followed by the family (Arabic number), subfamily (letter), and gene (Arabic number), for example, UGT1A1. UGT subfamily 1A1 and UGT family 2B are important in both
Drugs Metabolized by UGTs 1A1
1A3
1A4
1A6
1A9
2B7
2B15
acetaminophen buprenorphine ethinylestradiol SN-38 telmisartan
buprenorphine clozapine cyproheptadine diphenhydramine losartan NSAIDs valproate
chlorpromazine clozapine imipramine lamotrigine meperidine olanzapine
acetaminophen naproxen
acetaminophen AZT dapsone entacapone labetalol NSAIDs propranolol propofol talcapone
buprenorphine chloramphenicol codeine cyclospoine epirubicin lorazepam losartan morphine oxycodone oxazepam temazepam valproate
dinestrol phenytoin metabolites
Psychosomatics 43:1, January-February 2002
77
Med-Psych Drug-Drug Interactions hepatic endogenous and drug metabolism. Hepatic UGT1As include UGT1A1, UGT1A3, UGT1A4, UGT1A6, and UGT1A9. They are all the product of a single gene located on chromosome 2. They share common exons 2–5, but exon 1 is unique to each isoenzyme. Because bilirubin is a substrate of only UGT1A1, genetic alterations are responsible for the congenital hyperbilirubinemias: Crigler-Najjar syndrome-type 1 (inactive protein) and Gilbert’s syndrome and Crigler-Najjar syndrome-type 2 (partially active protein). Individuals with Gilbert’s syndrome (GS, representing about 8%– 12% of Caucasian populations) have a fluctuating mild hyperbilirubinemia. Like slow metabolizers of CYP2D6, they have increased blood concentration of UGT1A1 substrates. They have been shown to have an increased risk of toxicity to the anticancer drug irinotecan because its active metabolite, SN-38, is conjugated by UGT1A1. Both ethinylestradiol (common in oral contraceptives) and buprenorphine are also substrates of UGT1A1, and individuals with GS may also have higher blood levels of these compounds and may be more likely to have increased side effects. Although telmisartan, an angiotensin II antagonist, is also conjugated by this UGT, only 1% of the drug is handled by this route. Unlike UGT1A, UGT2B genes are produced from separate genes. Located on chromosome 4, the UGT2B genes include UGT2B4, UGT2B7, UGT2B10, UGT2B1, UGTB17, and UGT2B28. Genetic polymorphisms are known to exist for UGT1A6, UGT2B4, UGT2B7 and UGT2B15, but their clinical significance has not yet been demonstrated. Like the P450s, UGTs have both unique and overlapping drug substrates, and they are vulnerable to drug 78
inhibition and induction. There may be competitive inhibition between substrates of the same UGT, and UGT inhibitors and inducers may be metabolized on other UGTs or through other metabolic systems. Table 1 includes many known substrates of UGTs and further examples may be found in a recently published review of UGTs by Liston (see Suggested Readings). At the present time, laboratory studies are routinely carried out to accurately profile P450 cytochromal involvement in the metabolism of particular drugs. This process has been discussed in previous editions of this column. Unfortunately, similar technologies are not yet available for drug studies of UGT substrates, inhibitors, and inducers. Drugs principally metabolized by CyP450 may have some UGT conjugation, and drugs principally metabolized by UGTs may have CyP450 metabolic contributions. As an example, the drug interaction between AZT and methadone is multidetermined. AZT is metabolized principally by UGT2B7 but also by the CyP450 3A4, which produces a myelotoxic metabolite. Methadone is a known inhibitor of CyP450 3A4, glucuronidation, and it also decreases the renal clearance of AZT. As new information about the UGTs emerge, it will be important for psychiatrists to stay informed in order to better understand how the UGTs are involved in clinically important drug interactions. —JRO
lite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 1999; 65:576–582 King CD, Rios GR, Green MD. UDPglucuronosyltransferases. Curr Drug Metabol 2000; 1:143–161 Liston HL, Markowitz JS, De Vane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 2001; 21:500–515 Tukey RH, Strassburg CP: Human UDPglucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2001; 40:581–616
2. Cholinesterase Inhibitors
Suggested Reading
The cholinesterase inhibitors (CIs) have become popular medications in the last 10 years. CIs are the only drugs approved for use in the treatment and management of Alzheimer’s dementia. This review is not intended to discuss the clinical indications of these drugs but rather as an overview of CI’s known clinically relevant DDI. CIs are typically prescribed for a geriatric population. This group of patients is often taking many other medications concomitantly. Therefore, it is important to know not only the clinical indications and side effects of these drugs but also their potential for DDI. Tacrine, the first of these compounds released in 1993, is rarely used now. This is primarily because of tacrine’s association with liver toxicity. In addition, tacrine needs be taken four times a day, making it the least convenient of the CIs (the others can be taken once or twice a day). Tacrine’s use has all but ceased since donepezil became available in 1997. Tacrine’s DDIs are summarized below.
Barbier O, Turgeon D, Girard C, et al: 3⬘azido-3⬘-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 2000; 28:497–502 Iyer L, Hall D, Das S et al: Phenotype-genotype correlation of in vitro SN-38 (active metabo-
1. Tacrine inhibits CyP450 1A2. Theophylline’s metabolism is highly dependent on 1A2. Theophylline levels are raised twofold with concomitant use of tacrine. Caffeine and pentoxiPsychosomatics 43:1, January-February 2002
Med-Psych Drug-Drug Interactions fylline, which are also very dependent on 1A2 for metabolic clearance, would be expected to have increased levels as well with tacrine use. 2. Tacrine levels increase significantly when co-administered with cimetidine, a known inhibitor of the CyP450 2D6, 3A4, and 1A2. 3. Tacrine levels may rise twice as high in women, possibly because 1A2 enzyme activity is less in women. 4. Smoking decreases tacrine levels by a third because of smoking’s induction of 1A2. Expect tacrine levels to increase in patients who quit smoking. Donepezil was introduced in 1997. Its DDI profile was a vast improvement over tacrine. It is metabolized by CyP450 2D6 and 3A4. Therefore, one can expect some DDI with donepezil. Most of these interactions appear to be minor because donepezil does not have a narrow margin of safety. In addition, unlike tacrine, donepezil does not inhibit or induce any metabolic enzymes that could affect the clearance of other drugs. Donepezil’s DDIs are summarized below. 1. Donepezil does not inhibit or induce any metabolic enzyme significantly. 2. Induction of 3A4 by phenobarbital, carbamazepine, oxcarbazepine, rifampin, phenytoin, and St. John’s Wort may all decrease levels of donepezil. 3. Known inhibitors of enzymes (ketoconazole for 3A4 and quinidine for 2D6) have been shown to increase donepezil levels in vitro. This could lead to enhanced side effects of donepezil, in particular nausea and diarrhea. Rivastigmine was introduced in 2000. It has a unique metabolic profile compared to the other CI drugs. RivasPsychosomatics 43:1, January-February 2002
tigmine is metabolized at its site of action—the cholinesterases—and this product is then cleared almost entirely by the kidneys. Grossberg et al. studied 22 classes of medications with rivastigmine for significant pharmacokinetic and pharmacodynamic DDI and found little or no clinically significant DDI with rivastigmine. The most recent addition to the CI drugs is galantamine, introduced in 2001. As with many modern drugs introduced in the last several years, the manufacturer studied many facets of potential DDIs, as well as polymorphic metabolic issues before galantamine’s release. Galantamine’s DDI profile is summarized below. 1. Galantamine does not inhibit or induce any metabolic enzymes. 2. No single metabolic/clearance pathway predominates. This means that the drug is less likely to have problems with other drugs inhibiting or inducing metabolic enzymes. 3. Known inhibitors of 2D6 (fluoxetine, paroxetine, quinidine, and cimetidine) and 3A4 (erythromycin and ketoconazole) increase AUC by 10%– 40%, but the clinical significance of these DDIs appears to be of small significance. —SCA Suggested Reading
Eisai, Inc.: Aricept (donepezil hydrochloride) tablets (package insert). Teaneck, NJ, Eisai, Inc., December, 2000 Parke Davis Pharmaceuticals, Ltd.: Cognex (tacrine hydrochloride) capsules (package insert). Morris Plains, NJ, Parke Davis Pharmaceuticals, Ltd., April, 2000 Novartis Pharmaceuticals Corporation: Exelon (rivastigmine tartrate) capsules (package insert). East Hanover, NJ, Novartis Pharmaceuticals Corporation, January, 2001 Grossberg GT, Stahelin HB, Messina JC, et al: Lack of adverse pharmacodynamic drug interactions with rivastigmine and twentytwo classes of medications. Int J Geriatr Psychiatry 2000; 15:242–247
Nordberg A, Svensson AL: Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Saf 1998; 19:465–480 Janssen Pharmaceutica: Reminyl (galantamine hydrobromide) tablets (package insert). Titusville, NJ, Janssen Pharmaceutica Products, L.P., March, 2001 Zurad EG: New treatments of Alzheimer’s disease: a review. Behavioral Health Trends 2001; 13:27–40
3. HMG-CoA Reductase Inhibitors: Commonly Referred to as ‘‘Statins’’ Hydroxymethylglutaryl-coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) decrease plasma cholesterol levels by inhibiting cholesterol synthesis in the liver. Inhibition of HMG-CoA reductase, the enzyme responsible for cholesterol synthesis is the pharmacodynamic mechanism of the statins. Toxicity of the statins may lead to myopathy, muscle toxicity, and rhabdomyolysis. The side effects of the statins include myopathy, evidenced by muscle pain, weakness, lethargy, and in some cases a greater than 10-fold increase in serum creatine kinase. The incidence of myopathy is low, particularly in monotherapy. The incidence of side effects increases with higher doses or serum levels of the statins. Drugs that increase the chances of myopathy include the fibrates, nicotinic acid, cholestyramine, cholestanol (these interact via unclear mechanisms), and drugs which inhibit metabolism of some statins dependent on CyP450 3A4 and 2C9 for metabolism. Table 3 reviews the DDIs of the statins and the CyP450 enzymes needed for effective metabolism of the statins. Most statins require CyP450 3A4 for effective metabolism and avoidance of myopathy, except for fluvastatin, which is metabolized at 2C9. Of note, pravastatin is only partially metabolized by 3A4 and most of the drug is eliminated by the kidney unchanged. 79
Med-Psych Drug-Drug Interactions Cerivastatin (Baycol) was recently removed from the U.S. market by the manufacturer because of numerous reports of side effects and rhabdomyolysis. We erroneously suggested that cerivastatin was a ‘‘safer’’ statin in an earlier writing (Cozza KL and Armstrong SC, 2001) because it was felt that cerivastatin’s greater bioavailability and greater potency at lower doses protected against the potential for DDIs with 3A4 inhibitors. All patients on statins other than pravastatin need to be warned that TABLE 2.
flucan娂), fluvoxamine (Luvox娂), and ritonavir. There are many moderate or mild inhibitors of 3A4 that are prescribed more frequently than the potent inhibitors simultaneously with the HMG-CoA reductase inhibitors, and these include beta-blockers and calcium-channel blockers among others. Boger provides a thoroughly readable review of this topic and includes ‘‘focused’’ sections on particular patient populations: cardiac, diabetic, renal disease, and neurology patients.
they may have serious interactions with potent inhibitors of CyP450 enzymes, and these patients should be monitored for such an interaction. The potent inhibitors of 3A4 are itraconazole (Sporanox娂), ketoconazole, nefazodone (Serzone娂), ritonavir (Norvir娂), ciprofloxacin (Cipro娂), clarithromycin (Biaxin娂), erythromycin, cyclosporin, efavirenz (Sustiva娂), lopinavir/ritonavir (Kaletra娂), and grapefruit juice. The potent inhibitors of 2C9 are fluconazole (Di-
Pharmacokinetic summary of Cholinesterase Inhibitors Tacrine (Cognex娂)
Year available Plasma 1⁄2 life (hrs.) Elimination pathways
1993 2–4 Liver
Enzyme pathways involved Significant active metabolites Plasma protein bound (%) Decreased absorption with food Significant Drug-drug Interactions
Donepezil (Aricept娂)
Rivastigmine (Exelon娂)
Galantamine (Reminyl娂)
CyP450 1A2 and to lesser extent, 2D6 Yes (one) by 1A2
1997 70 Liver Kidney 17% CyP450 2D6, 3A4 and Glucuronidation No
2000 1.5 Local cholinesterasea and Kidney Cholinesterases
2001 6 Liver 50% and Kidney 50%
No
CyP450 2D6, 3A4 and Glucuronidation Yes (one) by 2D6
55–75%
96%
40%
0–18%
30–40%
No
Decreases absorption but does not significantly effect Cmax
ⳭⳭⳭⳭ
ⳭⳭ
Delays by 90 minutes absorption and decreases Cmax by 30%, increases AUC by 30% —
Ⳮ
Notes. —No significant clinically relevant DDI ⳭSome minor potential for clinically relevant DDI ⳭⳭPotential for clinically relevant DDI moderate ⳭⳭⳭⳭPotential for clinically relevant DDI is high
TABLE 3.
Potential DDI With HMG-CoA Reductase Inhibitorsa
CyP450 3A4 Inhibitors Itraconazole Erythromycin Ritonavir Verapamil/diltiazem/ nifedipine CyP450 2C9 Inhibitors diclofenac
Lovastatin (Mevacor娂)
Simvastatin (Zocor娂)
Atorvastatin (Lipitor娂)
Cerivastatin (Baycol娂)
Fluvastatin (Lescol娂)
Pravastatin (Pravochol娂)
AUCx20 CR AUCx3
AUCx10 AUCx6 ND
AUCx3 AUCx1.4 ND
AUCⳭ38% AUCⳭ51% ND
None* ND AUCx3
None* ND AUCx3
AUCx3
AUCx5
ND
None*
ND
None*
ND
ND
ND
ND
AUCx1.5
ND
Notes. AUCx ⳱ increase in area under the concentration curve * ⳱ investigated clinical study found no interaction ND ⳱ no published data available CR ⳱ case report of rhabdomyolysis, but no pharmacokinetics data a Adapted from Boger RH: Drug interactions of the statins and consequences for drug selection. Int J Clin Pharmacol Ther 2001; 39:369–382
80
Psychosomatics 43:1, January-February 2002
Med-Psych Drug-Drug Interactions Finally, the only statin that appears to be a potent inhibitor of any cytochrome enzyme is fluvastatin. It is a potent inhibitor in vivo and in vitro of CyP450 2C9 and has been shown to decrease clearance of 2C9 substrates such as diclofenac (which can also increase fluvastatin levels by its inhibition of 2C9), tolbutamide, glyburide, losartan, and potentially phenytoin and warfarin (see Table 3 for a summary). —KLC
Suggested Reading
Boger RH: Drug interactions of the statins and consequences for drug selection. Int J Clin Pharmacol Ther 2001; 39:369–382
Psychosomatics 43:1, January-February 2002
Cozza KL, Armstrong SC: Internal medicine, in Concise Guide to the Cytochrome P450 System. American Psychiatric Publishing Inc., Washington DC, 2001, pp 128–129 Hatanaka T: Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet 2000; 39:397–412 FDA Talk Paper: Bayer voluntarily withdraws Baycol. T01–34, August 8, 2001 Scripture CD, Pieper JA: Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet 2001; 40:263–281
Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is
an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are co- authors of The Cytochrome P450 System: Drug Interaction Principles for Medical Practice. Washington, DC, American Psychiatric Press, Inc., 2001. Dr. Oesterheld is Medical Director, The Spurwink School, Portland, ME. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or [email protected].
81
W
e review three topics in this edition of Med-Psych DDI Update. First, we have a guest reviewer, Dr. Jessica R. Oesterheld, who informs us of a class of metabolic enzymes—the uridine diphosphate glucuronosyl transferases (UGTs). These enzymes are becoming more important to appreciate in terms of potential drug-drug interaction (DDI). We then review the cholinesterase inhibitors, the only drugs approved for treatment of Alzheimer’s dementia, and the hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, or ‘‘statin’’ drugs, which are used to aid in lowering cholesterol.
1. UGTs and Drug Interactions The hepatic P450 cytochromes have been center stage as the major culprits of most pharmacokinetic drug-drug interactions. Another superfamily of enzymes, the uridine diphosphate glucuronosyl transferases (UGTs) are beginning to emerge as challenging. Because it was only in 1997 that a UGT nomenclature was developed, data
TABLE 1. UGT
about them are at the stage that P450 cytochromes facts were about 10 years ago. Psychiatrists should know the basics about UGTs because some important medical and psychiatric drugs use these pathways, and they may interact with each other. P450 cytochromes begin the process of metabolism of lipid-soluble drugs to increasingly water-soluble metabolites so that drugs can be inactivated and excreted in the bile or urine. P450 cytochromes (Phase 1) break off part of the drug and insert or uncover a molecule (usually oxygen) to expose ‘‘a handle’’ so that conjugating enzymes (Phase 2) can form a link to that handle via a transferring enzyme. The most abundant conjugate is a sugar, glucuronic acid, and the UGTs are found close to the P450 cytochromes in the endoplasmic reticulum. Many important endogenous substrates such as bilirubin, bile acids, and most steroids are substrates of UGTs, as are more than 350 exogenous compounds. Drugs commonly encountered by psychiatrists who work in medical-surgical settings that are primarily handled by the UGTs include lamotrigine, valproate, nonsteroidal anti-inflammatory drugs, 3⬘-azido-3⬘-deoxythimidine (AZT), and morphine (see Table 1).
Most drugs are metabolized via both Phase 1 and Phase 2 processes, but some drugs that already have a ‘‘handle’’ are directly conjugated by UGTs. Psychiatrists are already aware that most benzodiazepines are first metabolized by the P450 system and then glucuronidated. Lorazepam, oxazepam, and temazepam are directly glucuronidated, making them the preferential benzodiazepines to be used in patients with hepatic disease because UGTs are less affected than P450s. Most glucuronidated drugs are inactive, but there are notable exceptions (e.g., morphine-6-glucuronate is 50 times more potent than morphine). UGTs are also found throughout the gastrointestinal tract, kidney, and brain and elsewhere in the body. UGT amino acids have been sequenced, and a nomenclature has been developed based on amino acid similarity. The website for the committee responsible for naming UGTs is located at http://www.unisa.edu.au/pharm_medsci /Gluc_trans/default.htm. Identical to the nomenclature of the P450s, the root symbol is followed by the family (Arabic number), subfamily (letter), and gene (Arabic number), for example, UGT1A1. UGT subfamily 1A1 and UGT family 2B are important in both
Drugs Metabolized by UGTs 1A1
1A3
1A4
1A6
1A9
2B7
2B15
acetaminophen buprenorphine ethinylestradiol SN-38 telmisartan
buprenorphine clozapine cyproheptadine diphenhydramine losartan NSAIDs valproate
chlorpromazine clozapine imipramine lamotrigine meperidine olanzapine
acetaminophen naproxen
acetaminophen AZT dapsone entacapone labetalol NSAIDs propranolol propofol talcapone
buprenorphine chloramphenicol codeine cyclospoine epirubicin lorazepam losartan morphine oxycodone oxazepam temazepam valproate
dinestrol phenytoin metabolites
Psychosomatics 43:1, January-February 2002
77
Med-Psych Drug-Drug Interactions hepatic endogenous and drug metabolism. Hepatic UGT1As include UGT1A1, UGT1A3, UGT1A4, UGT1A6, and UGT1A9. They are all the product of a single gene located on chromosome 2. They share common exons 2–5, but exon 1 is unique to each isoenzyme. Because bilirubin is a substrate of only UGT1A1, genetic alterations are responsible for the congenital hyperbilirubinemias: Crigler-Najjar syndrome-type 1 (inactive protein) and Gilbert’s syndrome and Crigler-Najjar syndrome-type 2 (partially active protein). Individuals with Gilbert’s syndrome (GS, representing about 8%– 12% of Caucasian populations) have a fluctuating mild hyperbilirubinemia. Like slow metabolizers of CYP2D6, they have increased blood concentration of UGT1A1 substrates. They have been shown to have an increased risk of toxicity to the anticancer drug irinotecan because its active metabolite, SN-38, is conjugated by UGT1A1. Both ethinylestradiol (common in oral contraceptives) and buprenorphine are also substrates of UGT1A1, and individuals with GS may also have higher blood levels of these compounds and may be more likely to have increased side effects. Although telmisartan, an angiotensin II antagonist, is also conjugated by this UGT, only 1% of the drug is handled by this route. Unlike UGT1A, UGT2B genes are produced from separate genes. Located on chromosome 4, the UGT2B genes include UGT2B4, UGT2B7, UGT2B10, UGT2B1, UGTB17, and UGT2B28. Genetic polymorphisms are known to exist for UGT1A6, UGT2B4, UGT2B7 and UGT2B15, but their clinical significance has not yet been demonstrated. Like the P450s, UGTs have both unique and overlapping drug substrates, and they are vulnerable to drug 78
inhibition and induction. There may be competitive inhibition between substrates of the same UGT, and UGT inhibitors and inducers may be metabolized on other UGTs or through other metabolic systems. Table 1 includes many known substrates of UGTs and further examples may be found in a recently published review of UGTs by Liston (see Suggested Readings). At the present time, laboratory studies are routinely carried out to accurately profile P450 cytochromal involvement in the metabolism of particular drugs. This process has been discussed in previous editions of this column. Unfortunately, similar technologies are not yet available for drug studies of UGT substrates, inhibitors, and inducers. Drugs principally metabolized by CyP450 may have some UGT conjugation, and drugs principally metabolized by UGTs may have CyP450 metabolic contributions. As an example, the drug interaction between AZT and methadone is multidetermined. AZT is metabolized principally by UGT2B7 but also by the CyP450 3A4, which produces a myelotoxic metabolite. Methadone is a known inhibitor of CyP450 3A4, glucuronidation, and it also decreases the renal clearance of AZT. As new information about the UGTs emerge, it will be important for psychiatrists to stay informed in order to better understand how the UGTs are involved in clinically important drug interactions. —JRO
lite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 1999; 65:576–582 King CD, Rios GR, Green MD. UDPglucuronosyltransferases. Curr Drug Metabol 2000; 1:143–161 Liston HL, Markowitz JS, De Vane CL: Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 2001; 21:500–515 Tukey RH, Strassburg CP: Human UDPglucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2001; 40:581–616
2. Cholinesterase Inhibitors
Suggested Reading
The cholinesterase inhibitors (CIs) have become popular medications in the last 10 years. CIs are the only drugs approved for use in the treatment and management of Alzheimer’s dementia. This review is not intended to discuss the clinical indications of these drugs but rather as an overview of CI’s known clinically relevant DDI. CIs are typically prescribed for a geriatric population. This group of patients is often taking many other medications concomitantly. Therefore, it is important to know not only the clinical indications and side effects of these drugs but also their potential for DDI. Tacrine, the first of these compounds released in 1993, is rarely used now. This is primarily because of tacrine’s association with liver toxicity. In addition, tacrine needs be taken four times a day, making it the least convenient of the CIs (the others can be taken once or twice a day). Tacrine’s use has all but ceased since donepezil became available in 1997. Tacrine’s DDIs are summarized below.
Barbier O, Turgeon D, Girard C, et al: 3⬘azido-3⬘-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 2000; 28:497–502 Iyer L, Hall D, Das S et al: Phenotype-genotype correlation of in vitro SN-38 (active metabo-
1. Tacrine inhibits CyP450 1A2. Theophylline’s metabolism is highly dependent on 1A2. Theophylline levels are raised twofold with concomitant use of tacrine. Caffeine and pentoxiPsychosomatics 43:1, January-February 2002
Med-Psych Drug-Drug Interactions fylline, which are also very dependent on 1A2 for metabolic clearance, would be expected to have increased levels as well with tacrine use. 2. Tacrine levels increase significantly when co-administered with cimetidine, a known inhibitor of the CyP450 2D6, 3A4, and 1A2. 3. Tacrine levels may rise twice as high in women, possibly because 1A2 enzyme activity is less in women. 4. Smoking decreases tacrine levels by a third because of smoking’s induction of 1A2. Expect tacrine levels to increase in patients who quit smoking. Donepezil was introduced in 1997. Its DDI profile was a vast improvement over tacrine. It is metabolized by CyP450 2D6 and 3A4. Therefore, one can expect some DDI with donepezil. Most of these interactions appear to be minor because donepezil does not have a narrow margin of safety. In addition, unlike tacrine, donepezil does not inhibit or induce any metabolic enzymes that could affect the clearance of other drugs. Donepezil’s DDIs are summarized below. 1. Donepezil does not inhibit or induce any metabolic enzyme significantly. 2. Induction of 3A4 by phenobarbital, carbamazepine, oxcarbazepine, rifampin, phenytoin, and St. John’s Wort may all decrease levels of donepezil. 3. Known inhibitors of enzymes (ketoconazole for 3A4 and quinidine for 2D6) have been shown to increase donepezil levels in vitro. This could lead to enhanced side effects of donepezil, in particular nausea and diarrhea. Rivastigmine was introduced in 2000. It has a unique metabolic profile compared to the other CI drugs. RivasPsychosomatics 43:1, January-February 2002
tigmine is metabolized at its site of action—the cholinesterases—and this product is then cleared almost entirely by the kidneys. Grossberg et al. studied 22 classes of medications with rivastigmine for significant pharmacokinetic and pharmacodynamic DDI and found little or no clinically significant DDI with rivastigmine. The most recent addition to the CI drugs is galantamine, introduced in 2001. As with many modern drugs introduced in the last several years, the manufacturer studied many facets of potential DDIs, as well as polymorphic metabolic issues before galantamine’s release. Galantamine’s DDI profile is summarized below. 1. Galantamine does not inhibit or induce any metabolic enzymes. 2. No single metabolic/clearance pathway predominates. This means that the drug is less likely to have problems with other drugs inhibiting or inducing metabolic enzymes. 3. Known inhibitors of 2D6 (fluoxetine, paroxetine, quinidine, and cimetidine) and 3A4 (erythromycin and ketoconazole) increase AUC by 10%– 40%, but the clinical significance of these DDIs appears to be of small significance. —SCA Suggested Reading
Eisai, Inc.: Aricept (donepezil hydrochloride) tablets (package insert). Teaneck, NJ, Eisai, Inc., December, 2000 Parke Davis Pharmaceuticals, Ltd.: Cognex (tacrine hydrochloride) capsules (package insert). Morris Plains, NJ, Parke Davis Pharmaceuticals, Ltd., April, 2000 Novartis Pharmaceuticals Corporation: Exelon (rivastigmine tartrate) capsules (package insert). East Hanover, NJ, Novartis Pharmaceuticals Corporation, January, 2001 Grossberg GT, Stahelin HB, Messina JC, et al: Lack of adverse pharmacodynamic drug interactions with rivastigmine and twentytwo classes of medications. Int J Geriatr Psychiatry 2000; 15:242–247
Nordberg A, Svensson AL: Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Saf 1998; 19:465–480 Janssen Pharmaceutica: Reminyl (galantamine hydrobromide) tablets (package insert). Titusville, NJ, Janssen Pharmaceutica Products, L.P., March, 2001 Zurad EG: New treatments of Alzheimer’s disease: a review. Behavioral Health Trends 2001; 13:27–40
3. HMG-CoA Reductase Inhibitors: Commonly Referred to as ‘‘Statins’’ Hydroxymethylglutaryl-coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) decrease plasma cholesterol levels by inhibiting cholesterol synthesis in the liver. Inhibition of HMG-CoA reductase, the enzyme responsible for cholesterol synthesis is the pharmacodynamic mechanism of the statins. Toxicity of the statins may lead to myopathy, muscle toxicity, and rhabdomyolysis. The side effects of the statins include myopathy, evidenced by muscle pain, weakness, lethargy, and in some cases a greater than 10-fold increase in serum creatine kinase. The incidence of myopathy is low, particularly in monotherapy. The incidence of side effects increases with higher doses or serum levels of the statins. Drugs that increase the chances of myopathy include the fibrates, nicotinic acid, cholestyramine, cholestanol (these interact via unclear mechanisms), and drugs which inhibit metabolism of some statins dependent on CyP450 3A4 and 2C9 for metabolism. Table 3 reviews the DDIs of the statins and the CyP450 enzymes needed for effective metabolism of the statins. Most statins require CyP450 3A4 for effective metabolism and avoidance of myopathy, except for fluvastatin, which is metabolized at 2C9. Of note, pravastatin is only partially metabolized by 3A4 and most of the drug is eliminated by the kidney unchanged. 79
Med-Psych Drug-Drug Interactions Cerivastatin (Baycol) was recently removed from the U.S. market by the manufacturer because of numerous reports of side effects and rhabdomyolysis. We erroneously suggested that cerivastatin was a ‘‘safer’’ statin in an earlier writing (Cozza KL and Armstrong SC, 2001) because it was felt that cerivastatin’s greater bioavailability and greater potency at lower doses protected against the potential for DDIs with 3A4 inhibitors. All patients on statins other than pravastatin need to be warned that TABLE 2.
flucan娂), fluvoxamine (Luvox娂), and ritonavir. There are many moderate or mild inhibitors of 3A4 that are prescribed more frequently than the potent inhibitors simultaneously with the HMG-CoA reductase inhibitors, and these include beta-blockers and calcium-channel blockers among others. Boger provides a thoroughly readable review of this topic and includes ‘‘focused’’ sections on particular patient populations: cardiac, diabetic, renal disease, and neurology patients.
they may have serious interactions with potent inhibitors of CyP450 enzymes, and these patients should be monitored for such an interaction. The potent inhibitors of 3A4 are itraconazole (Sporanox娂), ketoconazole, nefazodone (Serzone娂), ritonavir (Norvir娂), ciprofloxacin (Cipro娂), clarithromycin (Biaxin娂), erythromycin, cyclosporin, efavirenz (Sustiva娂), lopinavir/ritonavir (Kaletra娂), and grapefruit juice. The potent inhibitors of 2C9 are fluconazole (Di-
Pharmacokinetic summary of Cholinesterase Inhibitors Tacrine (Cognex娂)
Year available Plasma 1⁄2 life (hrs.) Elimination pathways
1993 2–4 Liver
Enzyme pathways involved Significant active metabolites Plasma protein bound (%) Decreased absorption with food Significant Drug-drug Interactions
Donepezil (Aricept娂)
Rivastigmine (Exelon娂)
Galantamine (Reminyl娂)
CyP450 1A2 and to lesser extent, 2D6 Yes (one) by 1A2
1997 70 Liver Kidney 17% CyP450 2D6, 3A4 and Glucuronidation No
2000 1.5 Local cholinesterasea and Kidney Cholinesterases
2001 6 Liver 50% and Kidney 50%
No
CyP450 2D6, 3A4 and Glucuronidation Yes (one) by 2D6
55–75%
96%
40%
0–18%
30–40%
No
Decreases absorption but does not significantly effect Cmax
ⳭⳭⳭⳭ
ⳭⳭ
Delays by 90 minutes absorption and decreases Cmax by 30%, increases AUC by 30% —
Ⳮ
Notes. —No significant clinically relevant DDI ⳭSome minor potential for clinically relevant DDI ⳭⳭPotential for clinically relevant DDI moderate ⳭⳭⳭⳭPotential for clinically relevant DDI is high
TABLE 3.
Potential DDI With HMG-CoA Reductase Inhibitorsa
CyP450 3A4 Inhibitors Itraconazole Erythromycin Ritonavir Verapamil/diltiazem/ nifedipine CyP450 2C9 Inhibitors diclofenac
Lovastatin (Mevacor娂)
Simvastatin (Zocor娂)
Atorvastatin (Lipitor娂)
Cerivastatin (Baycol娂)
Fluvastatin (Lescol娂)
Pravastatin (Pravochol娂)
AUCx20 CR AUCx3
AUCx10 AUCx6 ND
AUCx3 AUCx1.4 ND
AUCⳭ38% AUCⳭ51% ND
None* ND AUCx3
None* ND AUCx3
AUCx3
AUCx5
ND
None*
ND
None*
ND
ND
ND
ND
AUCx1.5
ND
Notes. AUCx ⳱ increase in area under the concentration curve * ⳱ investigated clinical study found no interaction ND ⳱ no published data available CR ⳱ case report of rhabdomyolysis, but no pharmacokinetics data a Adapted from Boger RH: Drug interactions of the statins and consequences for drug selection. Int J Clin Pharmacol Ther 2001; 39:369–382
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Med-Psych Drug-Drug Interactions Finally, the only statin that appears to be a potent inhibitor of any cytochrome enzyme is fluvastatin. It is a potent inhibitor in vivo and in vitro of CyP450 2C9 and has been shown to decrease clearance of 2C9 substrates such as diclofenac (which can also increase fluvastatin levels by its inhibition of 2C9), tolbutamide, glyburide, losartan, and potentially phenytoin and warfarin (see Table 3 for a summary). —KLC
Suggested Reading
Boger RH: Drug interactions of the statins and consequences for drug selection. Int J Clin Pharmacol Ther 2001; 39:369–382
Psychosomatics 43:1, January-February 2002
Cozza KL, Armstrong SC: Internal medicine, in Concise Guide to the Cytochrome P450 System. American Psychiatric Publishing Inc., Washington DC, 2001, pp 128–129 Hatanaka T: Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet 2000; 39:397–412 FDA Talk Paper: Bayer voluntarily withdraws Baycol. T01–34, August 8, 2001 Scripture CD, Pieper JA: Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet 2001; 40:263–281
Dr. Armstrong is Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is
an HIV Psychiatrist with the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are co- authors of The Cytochrome P450 System: Drug Interaction Principles for Medical Practice. Washington, DC, American Psychiatric Press, Inc., 2001. Dr. Oesterheld is Medical Director, The Spurwink School, Portland, ME. Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple Street, Forest Grove, OR 97116, or [email protected].
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