Chapter 005. Principles of Clinical Pharmacology (Part 8)

Principles of Genetic Variation and Human Traits (See also Chaps. 62 and 64) Variants in the human genome resulting in variation in level of expression or function of molecules important for pharmacokinetics and pharmacodynamics are increasingly recognized. These may be mutations (very rare variants, often associated with disease) or polymorphisms, variants that are much more common in a population. Variants may occur at a single nucleotide [known as single nucleotide polymorphism (SNP)] or involve insertion or deletion of one or more nucleotides. They may be in the exons (coding regions) or introns (noncoding intervening sequences). Exonic polymorphisms may or...
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Chapter 005. Principles of Clinical Pharmacology (Part 8) Chapter 005. Principles of Clinical Pharmacology (Part 8) Principles of Genetic Variation and Human Traits (See also Chaps. 62 and 64) Variants in the human genome resulting invariation in level of expression or function of molecules important forpharmacokinetics and pharmacodynamics are increasingly recognized. These maybe mutations (very rare variants, often associated with disease) or polymorphisms,variants that are much more common in a population. Variants may occur at asingle nucleotide [known as single nucleotide polymorphism (SNP)] or involveinsertion or deletion of one or more nucleotides. They may be in the exons (codingregions) or introns (noncoding intervening sequences). Exonic polymorphismsmay or may not alter the encoded protein, and variant proteins may or may notdisplay altered function. Similarly, polymorphisms in intronic regions may or maynot alter gene expression and protein level. As variation in the human genome is increasingly well documented,associations are being described between polymorphisms and various traits(including response to drug therapy). Some of these rely on well-developed chainsof evidence, including in vitro studies demonstrating variant protein function,familial aggregation of the variant allele with the trait, and association studies inlarge populations. In other cases, the associations are less compelling. Identifyingreal associations is one challenge that must be overcome before the concept ofgenotyping to identify optimal drugs (or dosages) in individual patients prior toprescribing can be considered for widespread clinical practice. Nevertheless, theappeal of using genomic information to guide therapy is considerable. Rates of drug efficacy and adverse effects often vary among ethnic groups.Many explanations for such differences are plausible; genomic approaches havenow established that functionally important variants determining differences indrug response often display differing distributions among ethnic groups. Thisfinding may have importance for drug use among ethnic groups, as well as in drugdevelopment. Genetically Determined Drug Disposition and Variable Effects The concept that genetically determined variations in drug metabolismmight be associated with variable drug levels, and hence effect, was advanced atthe end of the nineteenth century, and the first examples of familial clustering ofunusual drug responses due to this mechanism were noted in the mid-twentiethcentury. Clinically important genetic variants have been described in multiplemolecular pathways of drug disposition (Table 5-1). A distinct multimodaldistribution of drug disposition (as shown in Fig. 5-6) argues for a predominanteffect of variants in a single gene in the metabolism of that substrate. Individualswith two alleles (variants) encoding for nonfunctional protein make up one group,often termed poor metabolizers (PM phenotype); many variants can produce sucha loss of function, complicating the use of genotyping in clinical practice.Individuals with one functional allele make up a second (intermediatemetabolizers) and may or may not be distinguishable from those with twofunctional alleles (extensive metabolizers, EMs). Ultra-rapid metabolizers withespecially high enzymatic activity (occasionally due to gene duplication; Fig. 5-6)have also been described for some traits. Many drugs in widespread use can inhibitspecific drug disposition pathways (Table 5-1), and so EM individuals receivingsuch agents can respond like PM patients (phenocopying). Polymorphisms ingenes encoding drug uptake or drug efflux transporters may be another contributorto variability in drug delivery to target sites and, hence, drug effects. However,loss-of-function alleles in these genes have not yet been described. CYP Variants CYP3A4 is the most abundant hepatic and intestinal CYP and is also theenzyme responsible for metabolism of the greatest number of drugs in therapeuticuse. CYP3A4 activity is highly variable (up to an order of magnitude) amongindividuals, but the underlying mechanisms are not yet well understood. A closelyrelated gene, encoding CYP3A5 (which shares substrates with CYP3A4), doesdisplay loss-of-function variants, especially in African-derived populations.CYP3A refers to both enzymes. CYP2D6 is second to CYP3A4 in the number of commonly used drugs thatit metabolizes. CYP2D6 is polymorphically distributed, with about 7% ofEuropean- and African-derived populations (but very few Asians) displaying thePM phenotype (Fig. 5-6). Dozens of loss-of-function variants in the CYP2D6 genehave been described; the PM phenotype arises in individuals with two such alleles.In addition, ultrarapid metabolizers with multiple functional copies of theCYP2D6 gene have been identified, particularly among northern Africans. CYP2D6 represents the main metabolic pathway for a number of drugs(Table 5-1). Codeine is biotransformed by CYP2D6 to the potent active metabolitemorphine, so its effects are blunted in PMs and exaggerated in ultrarapidmetabolizers. In the case of drugs with beta-blocking properties metabolized byCYP2D6, including ophthalmic timolol and the sodium channel–blockingantiarrhythmic propafenone, PM subjects display greater signs of beta blockade(including bradycardia and bronchospasm) than EMs. Further, in EM subjects,propafenone elimination becomes zero-order at higher doses; so, for example, atripling of the dose may lead to a tenfold increase in drug concentration. The oralhypoglycemic agent phenformin was withdrawn because it occasionally causedprofound lactic acidosis; this likely arose as a result of hi ...