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Pharmacogenomics and renal drug disposition in the newborn
Pharmacogenomics and Renal Drug Disposition in the Newborn Gaurav Kapur, Tej Mattoo, and J.V. Aranda
Genetic polymorphisms in the genes coding for drug metabolizing enzymes, drug transporters, and drug receptors are major determinants of an individual’s response to drugs. The potential interactions of pharmacogenomics of renal drug transporters and drug receptors with renal drug disposition and the immature kidneys are briefly reviewed. Examples of gene polymorphisms seen in the RAAS (renin angiotensin system), -adrenergic receptors, dopamine receptors and cytochrome P450 and their potential clinical impact are discussed. The human newborn has deficient hepatic and renal drug metabolism and disposition. This immaturity in drug-handling capacity may potentially be superimposed to genetic polymorphisms determining drug metabolism and transport thereby substantially increasing interpatient variability in drug dose requirements and in drug responses in the newborn. Pharmacogenomics is a tool that can be used to individualize drug therapy in newborns to minimize adverse drug effects and to optimize efficacy. © 2004 Elsevier Inc. All rights reserved. harmacogenetics and pharmacogenomics, the sciences that deal with the role of inheritance in the individual variations in drug response, promise to identify the appropriate drug and the right dose for each patient so as to maximize effectiveness and safety. This review focuses on the influence of pharmacogenetics as it relates to renal drug handling and their clinical application particularly those involving the rennin angiotensin system, and the adrenergic and dopaminergic systems. It focuses briefly on the factors influencing renal disposition of drugs in neonates and their potential inter-relationships with pharmacogenomics of drug handling in the newborns.
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Pharmacogenetics and Pharmacogenomics Pharmacogenetics is the study of genetically determined variations in individual’s response to drugs.1 The convergence of pharmacogenetics and rapid advances in human genomics has From the Departments of Pediatric Nephrology, Pharmacology and Pharmaceutical Sciences and the Pediatric Pharmacology Research Unit Network (PPRU), Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit MI. Address reprint requests to J. V. Aranda, MD, PhD, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit MI 48201; e-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0146-0005/04/2802-0007$30.00/0 doi:10.1053/j.semperi.2003.11.005
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resulted in pharmacogenomics, a term used to define the influence of DNA sequence variation(s) on the effect of a drug.2 Pharmacogenomics represents the shift of research paradigm brought about by the complete characterization of the Human Genome Project (HGP).3 As a result of the advances in the field of genomics (the study of entire set of human genes as part of the HGP) the traditional phenotype to genotype (pharmacogenetic) based research has reversed directions to the more promising genotype to phenotype (pharmacogenomic) flow of information. The individual response to a drug in terms of drug efficacy and toxicity is highly variable, which represents a major problem in the clinical practice. A meta-analysis of studies in US hospitals reveals that adverse drug reactions rank between the fourth and the sixth leading causes of death in hospital patients. Fatal drug reactions account for 100,000 deaths per year in the United States.4 Potential causes for such variability include 1) pathogenesis and severity of the disease being treated, 2) drug interactions, 3) patients age, 4) nutritional status, 5) renal and liver function, and 6) concomitant illness. Despite the potential implications of these clinical variables in drug metabolism, it is now recognized that inherited differences in drug metabolism and genetic polymorphism of targets of drug therapy, can have even greater influence on the efficacy and toxicity of medications.5,6
Seminars in Perinatology, Vol 28, No 2 (April), 2004: pp 132-140
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Pharmacogenomics Promises and Limitations The rapid advancement in the HGP and the field of pharmacogenomics has given birth to the concept of tailor made drug therapy, ie, drug therapy individualized to the genetic makeup of an individual, thereby minimizing their side effects and increasing their efficacy.7 Inter-individual differences in drug responses can be attributed to polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and or drug targets, and these accounts for the variability in drug therapy efficacy ranging from 25% to 80%.8 These genetic determinants of drug effects remain stable over patient’s lifetime and need to be evaluated only once. This knowledge is already making its way to the clinical practice, facilitated by increasing availability of CLIA (Clinical Laboratory Improvement Amendments)-certified genotyping tests from reference laboratories.6 Although these tests are available for single genes only, it is envisaged that in the future it will be possible to test for all the genes associated with drug efficacy and toxicity and translate this knowledge into treatment modalities that are individualized to a person’s genetic makeup, thereby increasing efficacy and decreasing side effects. However, the incorporation of this research into clinical practice presents considerable challenges. Genetic polymorphisms are the presence of variant or mutant genes in the population at a frequency of more than 1%.9 There are approximately 10 million single-nucleotide polymorphisms (SNP) in the human genome of which 4 million have been characterized.10 The translation of pharmacogenetic research into clinical medicine, apart from being challenging will be time consuming and also expensive.11 Pharmacogenomics and Drug Therapy Genetic polymorphisms focus on drug metabolizing enzymes,2 drug transporters that influence drug absorption, distribution and excretion,5,7,12 and receptors such as the dopamine and adrenergic receptor polymorphisms. Drug metabolizing reactions are primarily classified as phase I reactions (ie, oxidation, reduction, and hydrolysis) or phase II conjugation reactions (ie, acetylation, glucuronidation, sulfation, and methylation) and these convert lipid soluble drugs into
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more water soluble metabolites.13 There are many families of drug metabolizing enzymes; however, the most important and most extensively studied family is the cytochrome P450 enzymes.5,14 The functional consequences of genetic polymorphisms in the hepatic cytochrome P450s and the current knowledge regarding them have been reviewed.14,15 The kidneys are the principal organs for the excretion of drugs and their metabolites.13 This review focuses on the drug transporters identified in the kidneys and certain drugs and their transporters that have a predominant renal action.
Renal Drug Transporters The drug transporter systems in the kidneys play a critical role in the elimination of a large number of drugs, drug metabolites, and toxins, many of which are specifically harmful to the kidney. The mechanisms involved in this process are 1) transport of compounds across the basolateral membrane, 2) intracellular transport, and 3) secretion across the apical membrane into the lumen. Carrier-mediated transport of xenobiotics and their metabolites are confined to the proximal tubule,16 and separate carrier systems exist for the active secretion of organic anions and cations.17,18 The organic anion system is of particular importance as it mediates the final elimination of phase II biotransformation products (glucornides, sulfate esters, glutathione’s, glycine conjugates) into the urine.19 Basolateral Transporters OAT (organic anion transporter) family. The paraaminohippurate (PAH)/dicarboxylate exchanger, oat 1 has been cloned from rat and flounder by expression cloning in Xenopis laevis oocytes.20,21,22 The human ortholog of rat oat1 (OAT1) has 86% homogeneity23,24 and is the best studied of this family. The uptake of PAH is tertiary active process coupled to Na gradient. This gradient maintained by Na-K ATPase, drives the Na-dicarboxylate (SDCT2) co transport into the cell and enables uptake of PAH in exchange for dicarboxylate ion.16 ␣-ketoglutarate is the most abundant potential counter ion within the proximal tubular cell and may account for 40% of organic anion uptake,25
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whereas the rest is accounted for by Na/dicarboxylate exchanger.26 Oat1 has been shown to have a wide substrate specificity for endogenous substances such as cyclic nucleotides, prostaglandins, uric acid, and structurally diverse drugs such as -lactam antibiotics, methotrexate, and nonsteroidal anti-inflammatory drugs.27,28 Several other isoforms of the OAT family have been detected and reviewed,16,29 including oat2 and oat3/OAT3. In contrast to OAT1 both oat2 and oat3/OAT3 appear to be Na independent, suggesting that organic anion uptake is not driven by exchange against dicarboxylates.16 It is not clear whether oat2 and oat3 mediate efflux and/or reabsorption of organic anions because membrane localization and nephron distribution are not yet established.16 Multidrug resistance-associated protein family. These belong to ABC (ATP binding cassette) superfamily of transporters, and contains nine members, MRP1to9. The proteins catalyze an ATP dependent active transport of chemically unrelated compounds. The multidrug resistance-associated protein (MRP) family has been reviewed30 as has been aspects relating to multidrug resistance31,32 or with ABC transporters in general.33 In addition to neutral organic compounds, MRP1-3 also transport drugs conjugated to glutathione (GSH), glucornate or sulfate, and other organic anions such as methotrexate (MTX).30 MRP2 in the kidney has been suggested to contribute to cellular detoxification and to secretion of endogenous and xenobiotics compounds.29 Further studies are required to determine the transport characteristics of MRPs and define their role in the kidneys.16 MDR1/P-glycoprotein. A member of the ABC multidrug transporter family, it mediates extrusion of drugs such as steroids, cyclosporines, tacrolimus, digoxin, and other hydrophobic xenobiotics.34 In the kidney, glycoprotein is expressed on the brush border of the proximal tubule35 and the observation that digoxin is actively secreted by it is of importance in transporter mediated drug interactions.36 A mutation in the exon 26 of the MDR1 gene has been correlated with the expression levels and the function of intestinal P-glycoprotein. As a result the concentration of digoxin is higher in individuals homozygous for this mutation, which has been observed in 24%of the German population. A sulfate/anion exchanger (Sat 1) has
been recognized from the rat kidney and liver and is located at the basolateral membrane of the proximal tubules.37 Intracellular handling of drugs. Drugs accumulate in the proximal tubule and this is determined by active transport across the basolateral membrane, handling by proximal tubular cells and transport across the apical membrane into the lumen. The research on transcellular transport of organic anions is limited.16 It is postulated that anionic drugs interact with anion binding proteins, ligandin,38 or glutathione S-transferase B,39 and these may be involved in transcellular drug trafficking.38,40 However, more recent data on the role of binding proteins are not available.16 Biotransformation of the intracellular anionic drugs may be an important pathway of renal drug disposition. The pathways reported involve oxidative, reductive, and hydrolytic (phase I reactions) and conjugation to glucorunide, sulfate, or reduced glutathione (phase II reactions) and have maximal activity localized in the proximal tubule.41-43 Apical transport systems. MRP2 this is the most extensively studied member of the MRP family and has been identified in the brush border membranes of segments S1, S2, and S3 of rat kidney proximal tubules.44 MRP2 in the kidney has been suggested to contribute to the secretion of endogenous and xenobiotics anionic compounds, most of which are conjugates from blood into urine.29 The absence of MRP2 in the human liver results in Dubin Johnson syndrome.45 Organic anion transport polypeptides. These include the organic anion transport polypeptides (OATP)1, 3, and 5 and the kidney specific OATK-1and OATK-2.16,19 These transporters are Na and ATP independent. The OATP are bidirectional transporters, and it is not yet certain whether they are involved in the reabsorption rather than the efflux of the anionic compounds.19 H-Peptide cotransporters PEPT1 and PEPT2. These are involved in the H ion dependent transport of compounds such as anticancer drugs (bestatin, deltaaminovulinic acid), prodrugs (L-dopa-Lphe, L-valazidothymidine), ACE inhibitors, and b-lactam antibiotics such as cephalosporin’s and penicillins.46 Transporter pharmacogenomics is a rapidly developing field. The substrates of the transport-
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ers have to be elucidated in detail and mutations of transporters, particularly those involved in reuptake of serotinin, dopamine, and GABA are presently being studied with regard to clinically relevant changes in drug response. The knowledge of transport variants is limited; however, the polymorphism could have major impact in the requirement for individual dose adjustments for carriers of the mutation as highlighted by digoxin.
Drug Receptors RAAS Gene Polymorphisms The gene polymorphisms of the RAAS (reninangiotensin aldosterone system) studied are ACE enzyme insertion(I)/deletion(D), angiotensinogen gene M235T polymorphism, A1166C polymorphism of the angiotensin II type 1 receptor (AT1-A1166C) and aldosterone syntase (CYP11B2)-344C/T and intron 2W/C polymorphisms. The ACE gene is located on chromosome 17, and the polymorphism is characterized by the presence (I) or absence (D) of a 287-base pair alu repeat within intron 16.47 The polymorphism is located in an intron and thus it is believed to be a neutral marker in strong linkage disequilibrium with 1 or more unknown functional variants located in or close to the ACE gene.48 The D allele is associated with higher plasma ACE levels and this in turn becomes critical in the determination of angiotensins and kinin levels in tissue interstitium and peripheral circulation.49 This genetically driven increase in ACE has been linked to progression of cardiovascular and renal glomerulopathies and tubulointerstitial diseases.50-53 This has been extrapolated to clinical use by studies showing better treatment response in patients with DD genotype in coronary endothelial dysfunction in patients with atherosclerosis and its risk factors,54 renoprotective treatment in hypertensive albuminuric IDDM patients,55 renoprotection in chronic proteinuric nephropathies,56 and regression of left ventricular hypertrophy.57 The ACE gene polymorphism has also been associated with congenital hypo-dysplastic kidneys,58 and also shown to be a significant risk factor for renal parenchymal damage in primarily nonglomerular diseases.59
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These polymorphisms have been evaluated together in patients with essential hypertension,60 mild renal deficiency,61 progression of chronic renal insufficiency,62 and determinant of post transplant renal dysfunction and hypertension.63 Overall the benefits of ACE inhibition in slowing the progression of chronic renal insufficiency in nephropathies of divergent renal etiologies64 suggest that RAAS benefits may not be disease specific, and further studies will be required to explain its potential usefulness in other states.  adrenergic receptor pharmacogenetics. The human 2AR is encoded by an intronless gene, with a coding block of 1239 nucleic acids and within this region there are 9 known loci that vary in normal population.65 The most common polymorphisms are in the amino terminus of the receptor at amino acid position 16, where Arg or Gly can be found, and at position 27, where Gln or Glu is common.66 A rare variant has been found at position 34, with an allele frequency of ⬍ 1%. At position 164, Thr (wild type) or Ile can be found, although the latter is somewhat uncommon.66 The polymorphisms at positions 16 and 27 do not alter agonist affinity or coupling to Gs67 compared to Ile-64 receptor that has an approximately 3-fold decreased affinity for isoproternol, epinephrine, and norepinephrine.68 Polymorphisms at position 16 and 27 do alter agonist promoted down regulation of receptor due to alterations in receptor degradation after the internalization step.67 1-adrenergic receptor gene has been localized to chromosome 10,69 and 2 common polymorphisms Ser49Gly and Arg389Gly have been identified.70 Genes coding adrenergic receptors are candidate loci for the inheritance of salt sensitivity trait for hypertension (especially in African Americans) because of the role of these receptors in the renal regulation of sodium excretion.71 Studies have reported the preliminary evidence of linkage of salt sensitivity with 2adrenergic locus.71,72 Whether these genes are expressed in the newborn and whether their expression impacts on neonatal renal handling of solutes and drugs remain to be studied. Dopaminergic receptor polymorphism. The dopamine receptors are the members of the superfamily of G-protein-coupled receptors. Dopamine is an endogenous catecholamine that binds to and activates ␣-and -adrenergic recep-
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tors and through widely distributed specific receptors it modulates the transmembrane flux of several ions, prolactin release, and functions such as nerve conduction, behavior, and movement.73 The dopamine receptors are G-protein coupled receptors and in the central nervous system have been divided into D1and D2based on their ability to stimulate (D1) and inhibit (D2) adenylate cyclase.74 Peripheral dopaminergic receptors have been divided into DA1 and DA2. The DA1 receptors have been localized to the smooth muscles of the vascular bed particularly in the renal and splanchnic arteries75 and proximal renal tubules,76 juxtaglomerular apparatus,77 and mesangial cells78. Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilaotry and natriuretic.75,76 It has been assumed that an aberrant renal dopaminergic system may play a role in pathogenesis of some forms of hypertension73,79,80 and the role of renal dopamine D1A (DRD1A) receptors has been studied in both animal models of hypertension and essential hypertension patients.81-83 DRD1A gene polymorphism has been studied in psychiatric diseases84,85 and in essential hypertension.86 Fenoldopam a selective peripheral dopamine receptor agonist has been reviewed for the treatment of hypertension and as a renal protective drug.87 Dopamine and dobutamine are used extensively in sick newborns. Whether these dopamine receptors are expressed early in the human kidneys and whether the genetic polymorphisms partly determine the efficacy and toxicity of these drugs remain to be studied. Diuretics, drugs with primarily renal site of action, too have been associated with clinically important drug gene interaction. ␣ adducin is a cytoskeletal protein that is critical for the assembly of actin-spectrin network and has been implicated in cell-signal transduction.88,89 The Gly460Trp variant of ␣ adducin gene has been associated with renal sodium retention and salt sensitive form of hypertension in some populations.89 Studies have shown that diuretic therapy is associated with a lower risk of combined myocardial infarction (MI) or stroke in carriers of the adducin gene variant.90 Neonatal drug metabolism and renal function. The biotransformation of drugs by neonatal liver is influenced by properties unique to the neonate, which include slower rate of biotransformation,
slower overall elimination, marked intrapatient variability in elimination, variable maturational changes, variable metabolism and disposition at different gestational ages, and presence of alternative pathways.91 As a result of these factors, the neonatal liver poorly metabolizes drugs and drug elimination relies heavily on the renal excretion. The most important variable affecting renal function in the neonate is the postconceptional age.92 At birth, the GFR is 30% of the adults93 and birth acts as a stimulus for maturation of renal function with maturation continuing till adult levels are reached by 3 to 5 months of age.92 This pattern of adaptation is not the same for the preterm infants and a slower temporal pattern of postnatal development is observed in them.94 This problem is compounded in very low birth weight infants by fewer glomeruli as nephrogenesis is completed by 34 weeks of life only.93 Renal blood flow is the determinant of the amount of drug that is delivered to the kidney and is influenced by the intrinsic renal maturation and the changing physiologic state of the newborn. The postnatal changes in RBF temporally match those of the GFR.95 The tubular function is more immature than GFR at birth, and the maturation occurs slowly.91 The neonatal disease states affect the kidney primarily by hypoxia. Hypoxia leads to renal vasoconstriction, which adversely affects the glomerular and tubular function.96 The altered renal perfusion status may also activate the rennin angiotensin system resulting in oliguria and potentially causing renal failure.91 The ontogeny of the OA secretion is central to understanding how children compared to adults handle the anionic drugs. This ontogeny of the renal OA has till now been studied indirectly through physiology,97 and based predominantly on the inability of the kidneys to eliminate drug most likely secondary to immaturity. Studies on PAH secretion have demonstrated that OA secretion is low at birth98-100 increases over the first few weeks of neonatal life and then declines to adult levels.101,102 This increase in OA secretion represents the specific maturation of the transport system and is independent of the increase in renal mass.13 The OA transport activity varies not only with development but also with exposure to substrate (organic acids)103,104 and certain hormones.105 The susceptibility to induction seems to be restricted particular peri-
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ods in the newborn and varies with species.97,106 Evaluation of the developmental expression of OAT1, OAT2, and OAT3 showed a more or less coordinated appearance of the mRNAs for each of these proteins during development of the renal proximal tubule.107
Future Perspectives Individualized Drug Therapy and Polygenic Inheritance The convergence of the advances in the field of pharmacogenomics and human genetics will potentially identify the polygenic variations involved in the uptake, distribution, metabolism, and action of various drugs. These advances allow the physicians and health care givers to individualize the drug therapy based on the patient’s genetic makeup and thereby select the most appropriate drug, the optimal dose, and minimize or prevent side effects. There may be an increased focus on the polygenic nature of the inherited component of drug response. Approaches for elucidating polygenic determinants of drug response include the use of anonymous single nucleotide polymorphism maps to perform genome wide searches for polymorphisms associated with drug effects, and candidate gene strategies based on existing knowledge of a medications mechanism of action and pathways of metabolism and disposition.7 Proteomic studies are evolving strategies for identifying the genes that may influence drug response. Proteomics is the study of cellular protein interactions and its basis lies in the fact that functional dysregulation of proteins is fundamental to human disease. One of the goals of proteomics is to characterize the information flow in the cell and the organism. The role of renal transporters in drug handling has been established, and these transporters can be cloned and expressed in highly controlled systems. This allows the elucidation of the site of expression, pharmacokinetic properties of the transporters, and the role it plays in the effectiveness of the clinical treatment or in the adverse clinical affect. Renal drug handling in the newborn needs further studies in the future. The kidneys are the major site of drug disposition and although morphology and structure have been relatively well studied, little is known
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about the development and maturation of the proximal tubule.
Renal Drug Transporters Expression Tubulogenesis The ontogeny of the renal drug transporters is yet to be elucidated, as is the expression of the relevant genes in the premature and full-term newborns. The coordinated expression of transporter proteins and proximal tubule development points to a common regulatory pathway for expression. The elucidation of these regulatory pathways and factors influencing them will provide insight into mechanisms involved with drug disposition by the kidney. This will also help in understanding the clinical differences in drug handling a related to maturation of renal function in neonates (preterm and term), children, and adults. Disease States The alteration of OAT transporters expression in disease states such as renal failure, conditions of stress associated with sick neonates offers future research perspectives. These have obvious clinical implications as factors influencing drug metabolism in disease states can be identified and optimize drug therapy. The homologous nature of drug transporters, the many identified isoforms with overlapping drug specificities are the other aspects of this amazing puzzle that may be answered after the expression of these transporters in maturation and disease states has been elucidated. Renal Drug Receptors The clinical implications of drug receptors as related to the kidneys have been elucidated in the text with special reference to the RAAS, -adrenergic, dopaminergic and the diuretics. These polymorphisms help to identify the genetic factors influencing disease states and thereby optimizing treatment by the use of drugs that affect these pathways. Another area of polymorphism important for the kidneys is the potassium channel polymorphism at present clinically associated with the long QT syndrome. Studies on pharmacogenomics in the context of the immature neonatal kidneys will allow the individualization of drug therapy in the new-
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borns thereby eliminating or minimizing toxicity and side effects while maximizing drug efficacy.
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itors and angiotensin II receptor antagonists in interstitial scarring. Kidney Int 63:S111-S114, 1997 Prasad A, Narayanan S, Husain S, et al: Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition. Circulation 102:35-41, 2000 Jacobsen P, Rossing K, Rossing P, et al: Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney Int 53:10021006, 1998 Perna A, Ruggeneti P, Testa A, et al: ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies. Kidney Int 57:274-281, 2000 Kohno M, Yokokawa K, Minami M, et al: Association between angiotensin-converting enzyme polymorphism and regression of left ventricular hypertrophy in patient’s treated with angiotensin-converting enzyme inhibitors. Am J Med 106:544-549, 1999 Opezzo C, Barberis V, Edafonti A, et al: congenital anomalies of the kidney and urinary tract. G Ital Neferol 20:120-126, 2003 Hohenfeller K, Hunley TE, Brezinska R, et al: ACE I/D polymorphism predicts renal damage in congenital uropathies. Pediatr Nephrol 13:514-518, 1999 Pontremoli R, Ravera M, Viazzi F, et al: Genetic polymorphisms of the renin-angiotensin system and organ damage in essential hypertension. Kidney Int 57:561569, 2000 Wang J-G, Staessen J, Tizzoni L, et al: Renal function in relation to three candidate genes. Am J Kidney Dis 38:1158-1161, 2001 Coll E, Campos B, Nunez G, et al: Association between the A1166C polymorphism of the angiotensin II receptor type 1 and progression of chronic renal insufficiency. J Nephrol 16:357-364, 2003 Abdi R, Tran TB, Zee R, et al: Angiotensin gene polymorphism as a determinant of posttransplantation renal dysfunction and hypertension. Transplantation 72: 726-729, 2001 Bernadet-Monrozies P, Rostaing L, Kamar N, et al: The effect of angiotensin-converting enzyme inhibitors on the progression of chronic renal failure. Presse Med 31:1714-1720, 2000 Reihsaus E, Iniss M, Mac Intyre N, et al: Mutations in the gene encoding for 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 8:334-339, 1993 Ligett BS: 2-adrenergic receptor pharmacogenetics. Am J Respir Crit Care Med 161:S197-S201, 2000 Green S, Turki J, Iniss M, et al: Amino terminal polymorphisms of the human 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33:9414-9419, 1994 Green S, Cole G, Jacinto M, et al: A polymorphism of the human 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 268: 23116-23121, 2993 Hoehe MR, Otterud B, Hsieh WT, et al: Genetic mapping of adrenergic receptor genes in humans. J Mol Med 73:299-306, 1995 Maqbool A, Hall AS, Ball SG, et al: Common polymor-
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phisms of 1–adrenoceptor: Identification and rapid screening assay. Lancet 353:897, 1999 Svetky LP, Chen YT, McKeown SP, et al: Preliminary evidence of salt sensitivity in black Americans at the 2adrenergic receptor locus. Hypertension 29:918-922, 1997 Svetky LP, Timmons PZ, Emovon O, et al: Association of hypertension with the 2 and ␣2c10-adrenergic receptor genotype. Hypertension 27:1210-1215, 1996 Jose PA, Raymond JR, Bates MD, et al: The renal dopaminergic receptors. J Am Soc Nephrol 2:1265-1278, 1992 Kebabian JW, Calne DB: Multiple receptors for dopamine. Nature 277:93-96, 1979 Goldberg LI: Dopamine receptors and hypertension: Physiologic and pharmacologic implications. Am J Med 77:37-44, 1984 (supppl 4A) Hughes JM, Beck TR, Rose CR, et al: Selective dopamine-1 receptor stimulation produces natriuresis by a direct tubular action. J Hypertens Suppl 4:S106-S108, 1986 Antonipillai I, Broers MI, Lang D: Evidence that specific dopamine-1 receptor action is involved in dopamine-induced renin release. Hypertension 13:463-468, 1989 Schultz PJ, Sedor JR, Abboud HE: Dopaminergic stimulation of c-AMP accumulation in cultured rat mesangial cells. Am J Physiol 253:H358-H364, 1987 Hussain T, Lokhandwala MF: Renal dopamine receptor functions in hypertension. Hypertension 32:187-197, 1998 Missale C, Nash SR, Robinson SW, et al: Dopamine receptors: From structure to function. Physiol Rev 78: 189-225, 1998 Watanabe H, Ogura T, Hosoya M, et al: Developmental changes of kidney dopamine receptors in spontaneously hypertensive rats. Res Commun Mol Pathol Pharmacol 87:333-344, 1995 Sidhu A, Kumar U, Uh M, et al: Diminished expression of renal dopamine receptors D1A receptors in the kidney inner medulla of the spontaneously hypertensive rats. J Hypertens 16:601-608, 1998 Sanada H, Jose PA, Hazen-Martin D, et al: Dopamine-1 receptor coupling defect in renal proximal tubule cells in hypertension. Hypertension 33:1036-1042, 1993 Cichon S, Nothen MM, Rietschel M, et al: Single strand conformation analysis of the dopamine D1 receptor gene reveals no significant mutation in patients with schizophrenia and bipolar affective disorder. Am J Med Genet 67:424-428, 1996 Kojima H, Ohmori O, Shinkai T, et al: Dopamine D1 receptor gene polymorphism and schizophrenia in Japan. Am J Med Genet 88:116-119, 1999 Sato M, Soma M, Nakayama T, et al: Dopamine D1 receptor gene polymorphism is associated with essential hypertension. Hypertension 36:183-186, 2000 Wood JJA: Fenoldopam-A selective peripheral dopamine receptor agonist for the treatment of severe hypertension. N Eng J Med 345:1548-1557, 2001 Matsuoka Y, Li X, Bennett V: Adducin: Structure, function and regulation. Cell Mol Life Sci 57:884-895, 2000 Ferrandi M, Bianchi G: Genetic mechanisms underlying the regulation of urinary sodium excretion and
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arterial blood pressure: The role of adducin. Acta Physiol Scand 168:187-193, 2000 Psaty BM, Smith N, Heckbert S, et al: Diuretic therapy, the ␣-Adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA 287:1680-1689, 2002 Nagourney BA, Aranda JV: Physiologic differences of clinical significance, in Polin RA, Fox WW (eds): Fetal and Neonatal Physiology (ed 2). Philadelphia, PA, Saunders, 1998, pp 239 –249 Drukker A, Guignard JP: Renal aspects of the term and preterm infant: A selective update. Curr Opin Pediatr 14:175-182, 2002 Aranda JV, Stern L: Clinical aspects of developmental pharmacology and toxicology. Pharmacol Ther 20:1, 1983 Vanpee M, Blennow M, Linne T, et al: Renal function in very low birth weight infants: Normal maturity reached during early childhood. J Pediatr 121:784-788, 1992 Jose PA, Haramati A, Fildes RD: Postnatal maturation of renal blood flow, Polin RA, Fox WW, (eds): Fetal and Neonatal Physiology (ed 2). Philadelphia, PA, Saunders, 1998, pp 1573-1578 Toth-Heyn P, Drukker A, Guignard JP: The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy. Pediatr Nephrol 14:227-239, 2000 Sweet DH, Bush KT, Nigam S: The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol 281:197-205, 2001 Calcagno PL, Rubin MI: Renal excretion of para-aminohippurate in infants and children. J Clin Invest 42: 1632, 1963 Jose P, Logan A, Slotkoff L, et al: Intrarenal blood flow distribution in canine puppies. Pediatr Res 5:337-344, 1971 Phelp DL, Omori K, Oh W: PAH clearance, sodium restriction and PAH extraction ratio in acidotic near term lambs treated with hypertonic sodium bicarbonate. Biol Neonate 28:57-64, 1976 Kaplan MR, Lewy JE: Stimulation of p-aminohippurate extraction in the maturing rabbit kidney. Pediatr Res 12:834-837, 1978 Rennick B, Hamilton B, Evans R: Development of renal tubular transporters of TEA and PAH in the puppy and piglet. Am J Physiol 201:743-746, 1961 Hook JB, Hewitt WR: Development of mechanisms for drug excretion. Am J Med 62:497-506, 1977 Hirsch GH, Hook JB: Maturation of renal organic transport: Substrate stimulation by penicillin. Science 165: 909-910, 1969 Braunlich H: Hormonal control of postnatal development of renal tubular transport of weak organic acids. Pediatr Nephrol 2:151-155, 1988 Hirsch GH, Hook JB: Maturation of renal organic acid transport: substrate stimulation by penicillin and paminohippurate (PAH). J Pharmacol Exp Ther 171: 103-108, 1970 Pavlova A, Skirai H, Leclerecq B, et al: Developmentally regulated expression of organic ion transporters NKT (OAT), OCT, OAT2 and Roct. Am J Physiol Renal Physiol 278:F635-F643, 2000
Genetic polymorphisms in the genes coding for drug metabolizing enzymes, drug transporters, and drug receptors are major determinants of an individual’s response to drugs. The potential interactions of pharmacogenomics of renal drug transporters and drug receptors with renal drug disposition and the immature kidneys are briefly reviewed. Examples of gene polymorphisms seen in the RAAS (renin angiotensin system), -adrenergic receptors, dopamine receptors and cytochrome P450 and their potential clinical impact are discussed. The human newborn has deficient hepatic and renal drug metabolism and disposition. This immaturity in drug-handling capacity may potentially be superimposed to genetic polymorphisms determining drug metabolism and transport thereby substantially increasing interpatient variability in drug dose requirements and in drug responses in the newborn. Pharmacogenomics is a tool that can be used to individualize drug therapy in newborns to minimize adverse drug effects and to optimize efficacy. © 2004 Elsevier Inc. All rights reserved. harmacogenetics and pharmacogenomics, the sciences that deal with the role of inheritance in the individual variations in drug response, promise to identify the appropriate drug and the right dose for each patient so as to maximize effectiveness and safety. This review focuses on the influence of pharmacogenetics as it relates to renal drug handling and their clinical application particularly those involving the rennin angiotensin system, and the adrenergic and dopaminergic systems. It focuses briefly on the factors influencing renal disposition of drugs in neonates and their potential inter-relationships with pharmacogenomics of drug handling in the newborns.
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Pharmacogenetics and Pharmacogenomics Pharmacogenetics is the study of genetically determined variations in individual’s response to drugs.1 The convergence of pharmacogenetics and rapid advances in human genomics has From the Departments of Pediatric Nephrology, Pharmacology and Pharmaceutical Sciences and the Pediatric Pharmacology Research Unit Network (PPRU), Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit MI. Address reprint requests to J. V. Aranda, MD, PhD, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit MI 48201; e-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0146-0005/04/2802-0007$30.00/0 doi:10.1053/j.semperi.2003.11.005
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resulted in pharmacogenomics, a term used to define the influence of DNA sequence variation(s) on the effect of a drug.2 Pharmacogenomics represents the shift of research paradigm brought about by the complete characterization of the Human Genome Project (HGP).3 As a result of the advances in the field of genomics (the study of entire set of human genes as part of the HGP) the traditional phenotype to genotype (pharmacogenetic) based research has reversed directions to the more promising genotype to phenotype (pharmacogenomic) flow of information. The individual response to a drug in terms of drug efficacy and toxicity is highly variable, which represents a major problem in the clinical practice. A meta-analysis of studies in US hospitals reveals that adverse drug reactions rank between the fourth and the sixth leading causes of death in hospital patients. Fatal drug reactions account for 100,000 deaths per year in the United States.4 Potential causes for such variability include 1) pathogenesis and severity of the disease being treated, 2) drug interactions, 3) patients age, 4) nutritional status, 5) renal and liver function, and 6) concomitant illness. Despite the potential implications of these clinical variables in drug metabolism, it is now recognized that inherited differences in drug metabolism and genetic polymorphism of targets of drug therapy, can have even greater influence on the efficacy and toxicity of medications.5,6
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Pharmacogenomics Promises and Limitations The rapid advancement in the HGP and the field of pharmacogenomics has given birth to the concept of tailor made drug therapy, ie, drug therapy individualized to the genetic makeup of an individual, thereby minimizing their side effects and increasing their efficacy.7 Inter-individual differences in drug responses can be attributed to polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and or drug targets, and these accounts for the variability in drug therapy efficacy ranging from 25% to 80%.8 These genetic determinants of drug effects remain stable over patient’s lifetime and need to be evaluated only once. This knowledge is already making its way to the clinical practice, facilitated by increasing availability of CLIA (Clinical Laboratory Improvement Amendments)-certified genotyping tests from reference laboratories.6 Although these tests are available for single genes only, it is envisaged that in the future it will be possible to test for all the genes associated with drug efficacy and toxicity and translate this knowledge into treatment modalities that are individualized to a person’s genetic makeup, thereby increasing efficacy and decreasing side effects. However, the incorporation of this research into clinical practice presents considerable challenges. Genetic polymorphisms are the presence of variant or mutant genes in the population at a frequency of more than 1%.9 There are approximately 10 million single-nucleotide polymorphisms (SNP) in the human genome of which 4 million have been characterized.10 The translation of pharmacogenetic research into clinical medicine, apart from being challenging will be time consuming and also expensive.11 Pharmacogenomics and Drug Therapy Genetic polymorphisms focus on drug metabolizing enzymes,2 drug transporters that influence drug absorption, distribution and excretion,5,7,12 and receptors such as the dopamine and adrenergic receptor polymorphisms. Drug metabolizing reactions are primarily classified as phase I reactions (ie, oxidation, reduction, and hydrolysis) or phase II conjugation reactions (ie, acetylation, glucuronidation, sulfation, and methylation) and these convert lipid soluble drugs into
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more water soluble metabolites.13 There are many families of drug metabolizing enzymes; however, the most important and most extensively studied family is the cytochrome P450 enzymes.5,14 The functional consequences of genetic polymorphisms in the hepatic cytochrome P450s and the current knowledge regarding them have been reviewed.14,15 The kidneys are the principal organs for the excretion of drugs and their metabolites.13 This review focuses on the drug transporters identified in the kidneys and certain drugs and their transporters that have a predominant renal action.
Renal Drug Transporters The drug transporter systems in the kidneys play a critical role in the elimination of a large number of drugs, drug metabolites, and toxins, many of which are specifically harmful to the kidney. The mechanisms involved in this process are 1) transport of compounds across the basolateral membrane, 2) intracellular transport, and 3) secretion across the apical membrane into the lumen. Carrier-mediated transport of xenobiotics and their metabolites are confined to the proximal tubule,16 and separate carrier systems exist for the active secretion of organic anions and cations.17,18 The organic anion system is of particular importance as it mediates the final elimination of phase II biotransformation products (glucornides, sulfate esters, glutathione’s, glycine conjugates) into the urine.19 Basolateral Transporters OAT (organic anion transporter) family. The paraaminohippurate (PAH)/dicarboxylate exchanger, oat 1 has been cloned from rat and flounder by expression cloning in Xenopis laevis oocytes.20,21,22 The human ortholog of rat oat1 (OAT1) has 86% homogeneity23,24 and is the best studied of this family. The uptake of PAH is tertiary active process coupled to Na gradient. This gradient maintained by Na-K ATPase, drives the Na-dicarboxylate (SDCT2) co transport into the cell and enables uptake of PAH in exchange for dicarboxylate ion.16 ␣-ketoglutarate is the most abundant potential counter ion within the proximal tubular cell and may account for 40% of organic anion uptake,25
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whereas the rest is accounted for by Na/dicarboxylate exchanger.26 Oat1 has been shown to have a wide substrate specificity for endogenous substances such as cyclic nucleotides, prostaglandins, uric acid, and structurally diverse drugs such as -lactam antibiotics, methotrexate, and nonsteroidal anti-inflammatory drugs.27,28 Several other isoforms of the OAT family have been detected and reviewed,16,29 including oat2 and oat3/OAT3. In contrast to OAT1 both oat2 and oat3/OAT3 appear to be Na independent, suggesting that organic anion uptake is not driven by exchange against dicarboxylates.16 It is not clear whether oat2 and oat3 mediate efflux and/or reabsorption of organic anions because membrane localization and nephron distribution are not yet established.16 Multidrug resistance-associated protein family. These belong to ABC (ATP binding cassette) superfamily of transporters, and contains nine members, MRP1to9. The proteins catalyze an ATP dependent active transport of chemically unrelated compounds. The multidrug resistance-associated protein (MRP) family has been reviewed30 as has been aspects relating to multidrug resistance31,32 or with ABC transporters in general.33 In addition to neutral organic compounds, MRP1-3 also transport drugs conjugated to glutathione (GSH), glucornate or sulfate, and other organic anions such as methotrexate (MTX).30 MRP2 in the kidney has been suggested to contribute to cellular detoxification and to secretion of endogenous and xenobiotics compounds.29 Further studies are required to determine the transport characteristics of MRPs and define their role in the kidneys.16 MDR1/P-glycoprotein. A member of the ABC multidrug transporter family, it mediates extrusion of drugs such as steroids, cyclosporines, tacrolimus, digoxin, and other hydrophobic xenobiotics.34 In the kidney, glycoprotein is expressed on the brush border of the proximal tubule35 and the observation that digoxin is actively secreted by it is of importance in transporter mediated drug interactions.36 A mutation in the exon 26 of the MDR1 gene has been correlated with the expression levels and the function of intestinal P-glycoprotein. As a result the concentration of digoxin is higher in individuals homozygous for this mutation, which has been observed in 24%of the German population. A sulfate/anion exchanger (Sat 1) has
been recognized from the rat kidney and liver and is located at the basolateral membrane of the proximal tubules.37 Intracellular handling of drugs. Drugs accumulate in the proximal tubule and this is determined by active transport across the basolateral membrane, handling by proximal tubular cells and transport across the apical membrane into the lumen. The research on transcellular transport of organic anions is limited.16 It is postulated that anionic drugs interact with anion binding proteins, ligandin,38 or glutathione S-transferase B,39 and these may be involved in transcellular drug trafficking.38,40 However, more recent data on the role of binding proteins are not available.16 Biotransformation of the intracellular anionic drugs may be an important pathway of renal drug disposition. The pathways reported involve oxidative, reductive, and hydrolytic (phase I reactions) and conjugation to glucorunide, sulfate, or reduced glutathione (phase II reactions) and have maximal activity localized in the proximal tubule.41-43 Apical transport systems. MRP2 this is the most extensively studied member of the MRP family and has been identified in the brush border membranes of segments S1, S2, and S3 of rat kidney proximal tubules.44 MRP2 in the kidney has been suggested to contribute to the secretion of endogenous and xenobiotics anionic compounds, most of which are conjugates from blood into urine.29 The absence of MRP2 in the human liver results in Dubin Johnson syndrome.45 Organic anion transport polypeptides. These include the organic anion transport polypeptides (OATP)1, 3, and 5 and the kidney specific OATK-1and OATK-2.16,19 These transporters are Na and ATP independent. The OATP are bidirectional transporters, and it is not yet certain whether they are involved in the reabsorption rather than the efflux of the anionic compounds.19 H-Peptide cotransporters PEPT1 and PEPT2. These are involved in the H ion dependent transport of compounds such as anticancer drugs (bestatin, deltaaminovulinic acid), prodrugs (L-dopa-Lphe, L-valazidothymidine), ACE inhibitors, and b-lactam antibiotics such as cephalosporin’s and penicillins.46 Transporter pharmacogenomics is a rapidly developing field. The substrates of the transport-
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ers have to be elucidated in detail and mutations of transporters, particularly those involved in reuptake of serotinin, dopamine, and GABA are presently being studied with regard to clinically relevant changes in drug response. The knowledge of transport variants is limited; however, the polymorphism could have major impact in the requirement for individual dose adjustments for carriers of the mutation as highlighted by digoxin.
Drug Receptors RAAS Gene Polymorphisms The gene polymorphisms of the RAAS (reninangiotensin aldosterone system) studied are ACE enzyme insertion(I)/deletion(D), angiotensinogen gene M235T polymorphism, A1166C polymorphism of the angiotensin II type 1 receptor (AT1-A1166C) and aldosterone syntase (CYP11B2)-344C/T and intron 2W/C polymorphisms. The ACE gene is located on chromosome 17, and the polymorphism is characterized by the presence (I) or absence (D) of a 287-base pair alu repeat within intron 16.47 The polymorphism is located in an intron and thus it is believed to be a neutral marker in strong linkage disequilibrium with 1 or more unknown functional variants located in or close to the ACE gene.48 The D allele is associated with higher plasma ACE levels and this in turn becomes critical in the determination of angiotensins and kinin levels in tissue interstitium and peripheral circulation.49 This genetically driven increase in ACE has been linked to progression of cardiovascular and renal glomerulopathies and tubulointerstitial diseases.50-53 This has been extrapolated to clinical use by studies showing better treatment response in patients with DD genotype in coronary endothelial dysfunction in patients with atherosclerosis and its risk factors,54 renoprotective treatment in hypertensive albuminuric IDDM patients,55 renoprotection in chronic proteinuric nephropathies,56 and regression of left ventricular hypertrophy.57 The ACE gene polymorphism has also been associated with congenital hypo-dysplastic kidneys,58 and also shown to be a significant risk factor for renal parenchymal damage in primarily nonglomerular diseases.59
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These polymorphisms have been evaluated together in patients with essential hypertension,60 mild renal deficiency,61 progression of chronic renal insufficiency,62 and determinant of post transplant renal dysfunction and hypertension.63 Overall the benefits of ACE inhibition in slowing the progression of chronic renal insufficiency in nephropathies of divergent renal etiologies64 suggest that RAAS benefits may not be disease specific, and further studies will be required to explain its potential usefulness in other states.  adrenergic receptor pharmacogenetics. The human 2AR is encoded by an intronless gene, with a coding block of 1239 nucleic acids and within this region there are 9 known loci that vary in normal population.65 The most common polymorphisms are in the amino terminus of the receptor at amino acid position 16, where Arg or Gly can be found, and at position 27, where Gln or Glu is common.66 A rare variant has been found at position 34, with an allele frequency of ⬍ 1%. At position 164, Thr (wild type) or Ile can be found, although the latter is somewhat uncommon.66 The polymorphisms at positions 16 and 27 do not alter agonist affinity or coupling to Gs67 compared to Ile-64 receptor that has an approximately 3-fold decreased affinity for isoproternol, epinephrine, and norepinephrine.68 Polymorphisms at position 16 and 27 do alter agonist promoted down regulation of receptor due to alterations in receptor degradation after the internalization step.67 1-adrenergic receptor gene has been localized to chromosome 10,69 and 2 common polymorphisms Ser49Gly and Arg389Gly have been identified.70 Genes coding adrenergic receptors are candidate loci for the inheritance of salt sensitivity trait for hypertension (especially in African Americans) because of the role of these receptors in the renal regulation of sodium excretion.71 Studies have reported the preliminary evidence of linkage of salt sensitivity with 2adrenergic locus.71,72 Whether these genes are expressed in the newborn and whether their expression impacts on neonatal renal handling of solutes and drugs remain to be studied. Dopaminergic receptor polymorphism. The dopamine receptors are the members of the superfamily of G-protein-coupled receptors. Dopamine is an endogenous catecholamine that binds to and activates ␣-and -adrenergic recep-
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tors and through widely distributed specific receptors it modulates the transmembrane flux of several ions, prolactin release, and functions such as nerve conduction, behavior, and movement.73 The dopamine receptors are G-protein coupled receptors and in the central nervous system have been divided into D1and D2based on their ability to stimulate (D1) and inhibit (D2) adenylate cyclase.74 Peripheral dopaminergic receptors have been divided into DA1 and DA2. The DA1 receptors have been localized to the smooth muscles of the vascular bed particularly in the renal and splanchnic arteries75 and proximal renal tubules,76 juxtaglomerular apparatus,77 and mesangial cells78. Dopamine facilitates the antihypertensive function of the kidney because it is both vasodilaotry and natriuretic.75,76 It has been assumed that an aberrant renal dopaminergic system may play a role in pathogenesis of some forms of hypertension73,79,80 and the role of renal dopamine D1A (DRD1A) receptors has been studied in both animal models of hypertension and essential hypertension patients.81-83 DRD1A gene polymorphism has been studied in psychiatric diseases84,85 and in essential hypertension.86 Fenoldopam a selective peripheral dopamine receptor agonist has been reviewed for the treatment of hypertension and as a renal protective drug.87 Dopamine and dobutamine are used extensively in sick newborns. Whether these dopamine receptors are expressed early in the human kidneys and whether the genetic polymorphisms partly determine the efficacy and toxicity of these drugs remain to be studied. Diuretics, drugs with primarily renal site of action, too have been associated with clinically important drug gene interaction. ␣ adducin is a cytoskeletal protein that is critical for the assembly of actin-spectrin network and has been implicated in cell-signal transduction.88,89 The Gly460Trp variant of ␣ adducin gene has been associated with renal sodium retention and salt sensitive form of hypertension in some populations.89 Studies have shown that diuretic therapy is associated with a lower risk of combined myocardial infarction (MI) or stroke in carriers of the adducin gene variant.90 Neonatal drug metabolism and renal function. The biotransformation of drugs by neonatal liver is influenced by properties unique to the neonate, which include slower rate of biotransformation,
slower overall elimination, marked intrapatient variability in elimination, variable maturational changes, variable metabolism and disposition at different gestational ages, and presence of alternative pathways.91 As a result of these factors, the neonatal liver poorly metabolizes drugs and drug elimination relies heavily on the renal excretion. The most important variable affecting renal function in the neonate is the postconceptional age.92 At birth, the GFR is 30% of the adults93 and birth acts as a stimulus for maturation of renal function with maturation continuing till adult levels are reached by 3 to 5 months of age.92 This pattern of adaptation is not the same for the preterm infants and a slower temporal pattern of postnatal development is observed in them.94 This problem is compounded in very low birth weight infants by fewer glomeruli as nephrogenesis is completed by 34 weeks of life only.93 Renal blood flow is the determinant of the amount of drug that is delivered to the kidney and is influenced by the intrinsic renal maturation and the changing physiologic state of the newborn. The postnatal changes in RBF temporally match those of the GFR.95 The tubular function is more immature than GFR at birth, and the maturation occurs slowly.91 The neonatal disease states affect the kidney primarily by hypoxia. Hypoxia leads to renal vasoconstriction, which adversely affects the glomerular and tubular function.96 The altered renal perfusion status may also activate the rennin angiotensin system resulting in oliguria and potentially causing renal failure.91 The ontogeny of the OA secretion is central to understanding how children compared to adults handle the anionic drugs. This ontogeny of the renal OA has till now been studied indirectly through physiology,97 and based predominantly on the inability of the kidneys to eliminate drug most likely secondary to immaturity. Studies on PAH secretion have demonstrated that OA secretion is low at birth98-100 increases over the first few weeks of neonatal life and then declines to adult levels.101,102 This increase in OA secretion represents the specific maturation of the transport system and is independent of the increase in renal mass.13 The OA transport activity varies not only with development but also with exposure to substrate (organic acids)103,104 and certain hormones.105 The susceptibility to induction seems to be restricted particular peri-
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ods in the newborn and varies with species.97,106 Evaluation of the developmental expression of OAT1, OAT2, and OAT3 showed a more or less coordinated appearance of the mRNAs for each of these proteins during development of the renal proximal tubule.107
Future Perspectives Individualized Drug Therapy and Polygenic Inheritance The convergence of the advances in the field of pharmacogenomics and human genetics will potentially identify the polygenic variations involved in the uptake, distribution, metabolism, and action of various drugs. These advances allow the physicians and health care givers to individualize the drug therapy based on the patient’s genetic makeup and thereby select the most appropriate drug, the optimal dose, and minimize or prevent side effects. There may be an increased focus on the polygenic nature of the inherited component of drug response. Approaches for elucidating polygenic determinants of drug response include the use of anonymous single nucleotide polymorphism maps to perform genome wide searches for polymorphisms associated with drug effects, and candidate gene strategies based on existing knowledge of a medications mechanism of action and pathways of metabolism and disposition.7 Proteomic studies are evolving strategies for identifying the genes that may influence drug response. Proteomics is the study of cellular protein interactions and its basis lies in the fact that functional dysregulation of proteins is fundamental to human disease. One of the goals of proteomics is to characterize the information flow in the cell and the organism. The role of renal transporters in drug handling has been established, and these transporters can be cloned and expressed in highly controlled systems. This allows the elucidation of the site of expression, pharmacokinetic properties of the transporters, and the role it plays in the effectiveness of the clinical treatment or in the adverse clinical affect. Renal drug handling in the newborn needs further studies in the future. The kidneys are the major site of drug disposition and although morphology and structure have been relatively well studied, little is known
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about the development and maturation of the proximal tubule.
Renal Drug Transporters Expression Tubulogenesis The ontogeny of the renal drug transporters is yet to be elucidated, as is the expression of the relevant genes in the premature and full-term newborns. The coordinated expression of transporter proteins and proximal tubule development points to a common regulatory pathway for expression. The elucidation of these regulatory pathways and factors influencing them will provide insight into mechanisms involved with drug disposition by the kidney. This will also help in understanding the clinical differences in drug handling a related to maturation of renal function in neonates (preterm and term), children, and adults. Disease States The alteration of OAT transporters expression in disease states such as renal failure, conditions of stress associated with sick neonates offers future research perspectives. These have obvious clinical implications as factors influencing drug metabolism in disease states can be identified and optimize drug therapy. The homologous nature of drug transporters, the many identified isoforms with overlapping drug specificities are the other aspects of this amazing puzzle that may be answered after the expression of these transporters in maturation and disease states has been elucidated. Renal Drug Receptors The clinical implications of drug receptors as related to the kidneys have been elucidated in the text with special reference to the RAAS, -adrenergic, dopaminergic and the diuretics. These polymorphisms help to identify the genetic factors influencing disease states and thereby optimizing treatment by the use of drugs that affect these pathways. Another area of polymorphism important for the kidneys is the potassium channel polymorphism at present clinically associated with the long QT syndrome. Studies on pharmacogenomics in the context of the immature neonatal kidneys will allow the individualization of drug therapy in the new-
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borns thereby eliminating or minimizing toxicity and side effects while maximizing drug efficacy.
19.
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