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Clinically important genetic variants have been described in multiple molecular pathways of drug disposition (Table 64-2). A distinct multimodal distribution of drug disposition (as shown in Fig. 64-1) argues for a predominant effect of variants in a single gene in the metabolism of that substrate. Individuals with two alleles (variants) encoding for nonfunctional protein make up one group, often termed poor metabolizers (PM phenotype). For most genes, many variants can produce such a loss of function, and assessing whether they are on the same or different alleles (i.e., the diplotype) can complicate the use of genotyping in clinical practice. Furthermore, some variants produce only partial loss of function, and the presence of more than one variant may be required to define a specific allele. Individuals with one functional allele, or multiple reduction of function alleles, make up a second (intermediate metabolizers) and may or may not be distinguishable from those with two functional alleles (normal metabolizers, often termed extensive metabolizers, EMs). Ultra-rapid metabolizers (UMs) with especially high enzymatic activity (occasionally due to gene duplication; Table 64-1 and Fig. 64-1) have also been described for some traits. Many drugs in widespread use can inhibit specific drug disposition pathways (see Chap. 63, Table 63-1), and so EM individuals receiving such inhibitors can respond like PM patients (phenocopying). Polymorphisms in genes encoding drug uptake or drug efflux transporters may be other contributors to variability in drug delivery to target sites and, hence, in drug effects.
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Members of the CYP3A family (CYP3A4, CYP3A5) metabolize the greatest number of drugs in therapeutic use. CYP3A4 activity is highly variable (up to an order of magnitude) among individuals, but non-synonymous coding region polymorphisms (those that change the encoded amino acid) are rare. Thus, the underlying mechanism likely reflects genetic variation in regulatory regions.
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Most subjects of European or Asian origin carry a polymorphism that disrupts splicing in the closely related CYP3A5 gene. As a result, these individuals display reduced CYP3A5 activity whereas CYP3A5 activity tends to be greater in subjects of African origin. Decreased efficacy of the antirejection agent tacrolimus in subjects of African origin has been attributed to more rapid CYP3A5-mediated elimination and a lower risk of vincristine-associated neuropathy has been reported in CYP3A5 “expressers.”
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CYP2D6 is second to CYP3A4 in the number of commonly used drugs that it metabolizes. CYP2D6 activity is polymorphically distributed, with 5–10% of European- and African-derived populations (but very few Asians) displaying the PM phenotype (Fig. 64-1). Dozens of loss-of-function variants in CYP2D6 have been described; the PM phenotype arises in individuals with two such alleles. In addition, ultra-rapid metabolizers with multiple functional copies of CYP2D6 have been identified especially in East Africa, the Middle East, and Oceania. PMs have slower elimination rates and lower clearance of substrate drugs; as a consequence (Fig. 64-1B), steady state concentrations are higher and the time taken to achieve steady state is longer than in EMs (see Chap. 63). Conversely, UMs display very low steady state parent drug concentrations and an abbreviated time to steady state.
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Codeine is biotransformed by CYP2D6 to the potent active metabolite morphine, so its effects are blunted in PMs and exaggerated in UMs. Deaths due to respiratory depression in children given codeine after tonsillectomy have been attributed to the UM trait, and the U.S. Food and Drug Administration (FDA) has revised the package insert to include a prominent “black box” warning against its use in this setting. In the case of drugs with beta-blocking properties metabolized by CYP2D6, greater signs of beta blockade (e.g., bronchospasm, bradycardia) are seen in PM subjects than in EMs. This can be seen not only with orally administered beta blockers such as metoprolol and carvedilol, but also with ophthalmic timolol and with the sodium channel–blocking antiarrhythmic propafenone, a CYP2D6 substrate with beta-blocking properties. Ultra-rapid metabolizers may require very high dosages of nortriptyline and other tricyclic antidepressants to achieve a therapeutic effect. Tamoxifen undergoes CYP2D6-mediated biotransformation to an active metabolite, so its efficacy may be in part related to this polymorphism. In addition, the widespread use of selective serotonin reuptake inhibitors (SSRIs) to treat tamoxifen-related hot flashes may also alter the drug’s effects because many SSRIs, notably fluoxetine and paroxetine, are also CYP2D6 inhibitors.
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The PM phenotype for CYP2C19 is common (20%) among Asians and rarer (2–3%) in other populations. The impact of polymorphic CYP2C19-mediated metabolism has been demonstrated with the proton pump inhibitor omeprazole, where ulcer cure rates with “standard” dosages were much lower in EM patients (29%) than in PMs (100%). Thus, understanding the importance of this polymorphism would have been important in developing the drug, and knowing a patient’s CYP2C19 genotype should improve therapy. CYP2C19 is responsible for bioactivation of the antiplatelet drug clopidogrel, and several large retrospective studies have documented decreased efficacy (e.g., increased myocardial infarction after placement of coronary stents or increased stroke or transient ischemic attacks) among subjects with one or two reduction of function alleles. In addition, some studies suggest that omeprazole and possibly other proton pump inhibitors phenocopy this effect by inhibiting CYP2C19.
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There are common variants in CYP2C9 that encode proteins with reduction or loss of catalytic function. These variant alleles are associated with increased rates of neurologic complications with phenytoin, hypoglycemia with glipizide, and reduced warfarin dose required to maintain stable anticoagulation. Rare patients homozygous for loss of function alleles may require very low warfarin dosages. Up to 50% of the variability in steady-state warfarin dose requirement is attributable to polymorphisms in CYP2C9 and in the promoter of VKORC1, which encodes the warfarin target with lesser contributions by genes controlling vitamin K metabolism such as CYP4F2. The angiotensin-receptor blocker losartan is a prodrug that is bioactivated by CYP2C9; as a result, PMs and those receiving inhibitor drugs may display little response to therapy.
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Individuals homozygous for loss of function alleles in dihydropyrimidine dehydrogenase, encoded by DPYD, are at high risk for severe toxicity when exposed to the substrate anticancer drug 5-Fluorouracil (5-FU), as well as to capecitabine and tegafur, which are metabolized to 5-FU. Dose reductions have been recommended in intermediate metabolizers.
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Thiopurine S-methyltransferase (TPMT) bioinactivates the antileukemic drug 6-mercaptopurine (6-MP) and 6-MP is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding inactive TPMT (1/300 individuals) predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-MP. On the other hand, homozygotes for fully functional alleles may display less anti-inflammatory or antileukemic effect with standard doses of the drugs.
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N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), which represents the activity of two genes, NAT1 and NAT2. Both enzymes transfer an acetyl group from acetyl coenzyme A to the drug; polymorphisms in NAT2 are thought to underlie individual differences in the rate at which drugs are acetylated and thus define “rapid acetylators” and “slow acetylators.” Slow acetylators make up ∼50% of European and African populations but are less common among East Asians. Slow acetylators have an increased incidence of the drug-induced lupus syndrome during procainamide and hydralazine therapy and of hepatitis with isoniazid.
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Individuals homozygous for a common promoter polymorphism that reduces transcription of uridine diphosphate glucuronosyltransferase (UGT1A1) have benign hyperbilirubinemia (Gilbert’s syndrome; Chap. 330). This variant has also been associated with diarrhea and increased bone marrow depression with the antineoplastic prodrug irinotecan, whose active metabolite is normally detoxified by UGT1A1-mediated glucuronidation. The antiretroviral atazanavir is a UGT1A1 inhibitor, and individuals with the Gilbert’s variant develop higher bilirubin levels during treatment. While this is benign, the hyperbilirubinemia can complicate clinical care because it may raise the question of whether coexistent hepatic injury is present.
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The risk for myotoxicity with simvastatin and possibly other statins appears increased with variants in SLCO1B1. Variants in ABCB1, encoding the drug efflux transporter P-glycoprotein, may increase digoxin toxicity. Variants in the uptake transporters MATE1 and MATE2 have been reported to modulate metformin’s glucose-lowering activity.