Chapter 005. Principles of Clinical Pharmacology (Part 9)

Transferase Variants One of the most extensively studied phase II polymorphisms is the PM trait for thiopurine S-methyltransferase (TPMT). TPMT bioinactivates the antileukemic drug 6-mercaptopurine. Further, 6-mercaptopurine is itself an active metabolite of the immunosuppressive azathioprine. Homozygotes for alleles encoding the inactive TPMT (1 in 300 individuals) predictably exhibit severe and potentially fatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On the other hand, homozygotes for fully functional alleles may display less antiinflammatory or antileukemic effect with the drugs.N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), which represents the activity of two genes, NAT-1 and NAT-2. Both enzymes...
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Chapter 005. Principles of Clinical Pharmacology (Part 9) Chapter 005. Principles of Clinical Pharmacology (Part 9) Transferase Variants One of the most extensively studied phase II polymorphisms is the PM traitfor thiopurine S-methyltransferase (TPMT). TPMT bioinactivates the antileukemicdrug 6-mercaptopurine. Further, 6-mercaptopurine is itself an active metabolite ofthe immunosuppressive azathioprine. Homozygotes for alleles encoding theinactive TPMT (1 in 300 individuals) predictably exhibit severe and potentiallyfatal pancytopenia on standard doses of azathioprine or 6-mercaptopurine. On theother hand, homozygotes for fully functional alleles may display less anti-inflammatory or antileukemic effect with the drugs. N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT), whichrepresents the activity of two genes, NAT-1 and NAT-2. Both enzymes transfer anacetyl group from acetyl coenzyme A to the drug; NAT-1 activity is generallyconstant, while polymorphisms in NAT-2 result in individual differences in the rateat which drugs are acetylated and thus define rapid acetylators and slowacetylators. Slow acetylators make up ~50% of European- and African-derivedpopulations but are less common among Asians. Slow acetylators have an increased incidence of the drug-induced lupussyndrome during procainamide and hydralazine therapy and of hepatitis withisoniazid. Induction of CYPs (e.g., by rifampin) also increases the risk ofisoniazid-related hepatitis, likely reflecting generation of reactive metabolites ofacetylhydrazine, itself an isoniazid metabolite. Individuals homozygous for a common promoter polymorphism thatreduces transcription of uridine diphosphate glucuronosyltransferase (UGT1A1)have benign hyperbilirubinemia (Gilberts syndrome; Chap. 297). This variant hasalso been associated with diarrhea and increased bone marrow depression with theantineoplastic prodrug irinotecan, whose active metabolite is normally detoxifiedby this UGT1A1-mediated glucuronidation. Variability in the Molecular Targets with Which Drugs Interact As molecular approaches identify specific gene products as targets of drugaction, polymorphisms that alter the expression or function of these drug targets—and thus modulate their actions in patients—are also being recognized. Multiplepolymorphisms identified in the 2-adrenergic receptor appear to be linked tospecific phenotypes in asthma and congestive heart failure, diseases in which 2-receptor function might be expected to determine prognosis. Polymorphisms in the2-receptor gene have also been associated with response to inhaled 2-receptoragonists, while those in the 1-adrenergic receptor gene have been associated withvariability in heart rate slowing and blood pressure lowering (Fig. 5-5B ). Inaddition, in heart failure, a common polymorphism in the 1-adrenergic receptorgene has been implicated in variable clinical outcome during therapy with the betablocker bucindolol. Response to the 5-lipoxygenase inhibitor zileuton in asthmahas been linked to polymorphisms that determine the expression level of the 5-lipoxygenase gene. Herceptin, which potentiates anthracycline-relatedcardiotoxicity, is ineffective in breast cancers that do not express the herceptinreceptor; thus, genotyping the tumor is a mechanism to avoid potentially toxictherapy in patients who would derive no benefit. Drugs may also interact with genetic pathways of disease, to elicit orexacerbate symptoms of the underlying conditions. In the porphyrias, CYPinducers are thought to increase the activity of enzymes proximal to the deficientenzyme, exacerbating or triggering attacks (Chap. 352). Deficiency of glucose-6-phosphate dehydrogenase (G6PD), most often in individuals of African orMediterranean descent, increases risk of hemolytic anemia in response toprimaquine and a number of other drugs that do not cause hemolysis in patientswith normal amounts of the enzyme (Chap. 101). Patients with mutations in theryanodine receptor, which controls intracellular calcium in skeletal muscle andother tissues, may be asymptomatic until exposed to certain general anesthetics,which trigger the syndrome of malignant hyperthermia. Certain antiarrhythmicsand other drugs can produce marked QT prolongation and torsades des pointes(Chap. 226), and in some patients this adverse effect represents unmasking ofpreviously subclinical congenital long QT syndrome. Polymorphisms that Modulate the Biologic Context Within Which theDrug-Target Interactions Occur The interaction of a drug with its molecular target is translated into aclinical action in a complex biologic milieu that is itself often perturbed bydisease. Thus, polymorphisms that determine variability in this biology mayprofoundly influence drug response, although the genes involved are notthemselves directly targets of drug action. Polymorphisms in genes important forlipid homeostasis (such as the ABCA1 transporter and the cholesterol estertransport protein) modulate response to 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, statins. In one large study, the combination ofdiuretic use combined with a variant in the adducin gene (encoding a cytoskeletalprotein important for renal tubular sodium absorption) decreased stroke ormyocardial infarction risk, while neither factor alone had an effect. Commonpolymorphisms in ion channel genes that are not themselves the target of QT-prolonging drugs may nevertheless influence the extent to which those drugsaffect the electrocardiogram and produce arrhythmias. These findings not onlypoint to new mechanisms for understanding drug action, but also can be used fordrug develop ...