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  Disease summary:

  
  
  
  
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    In this chapter, relatively common (>1% frequency) and ethically diverse genetic polymorphisms of drug-metabolizing cytochrome P450s (CYPs) will be reviewed. In general, these variants

    
    
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    Affect pharmacokinetics and response to drugs which are substrates of these enzymes

    
    
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    Are not usually associated with drug-independent clinical phenotypes

    
    
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    Have pharmacokinetic phenotypes categorized as poor, intermediate, normal (extensive), and ultrarapid metabolizer (UM)

    
    
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    Have clinical phenotypes which depend on the particular pharmacologic situation (drug, prodrug, therapeutic index, etc)

  
  

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  Differential diagnosis:

  
  
  
  
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    Intoxication, drug-drug interaction, allergy

  
  

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  Monogenic forms:

  
  
  
  
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    CYP polymorphisms are monogenically inherited as autosomal recessive (poor or intermediate metabolizers) or dominant (UMs) traits.

  
  

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  Twin studies:

  
  
  
  
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    The few mono- or dizygotic twin studies available indicate a large contribution of genetic factors to drug oxidation phenotype: heritability of antipyrine 4-hydroxylation rate, which is mainly catalyzed by CYP3A4, was estimated at 0.88 and that of the caffeine metabolic ratio, a marker of CYP1A2, at 0.72.

  
  

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  Environmental factors:

  
  
  
  
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    Drug-drug interactions (inhibition, induction), food constituents, circadian rhythm

  
  

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  Genome-wide associations:

  
  
  
  
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    GWAS revealed associations between CYP2C9 genotype and final dose of warfarin, an anticoagulant metabolized by the enzyme. Further, single-nucleotide polymorphisms (SNPs) in the regulatory region of the CYP1A locus were associated with habitual coffee consumption; this association is likely based on the major role of CYP1A2 as the rate-limiting enzyme for metabolism of caffeine.

  
  

The influence of heritable genetic polymorphisms in genes encoding drug-metabolizing CYPs on drug pharmacokinetics and drug response is well documented. Clinically relevant polymorphisms exist in CYPs 2B6, 2C9, 2C19, 2D6, and 3A4/5 (see later). In each of these genes, several individual SNPs are found in coding and/or noncoding gene regions, which influence either gene expression or enzymatic activity (Table 4-1). The CYP2D6 gene is also known for its numerous large-scale structural variants including a variety of gene copy number variants (CNV). Variants that lead to lower or higher expression of the enzyme are expected to decrease or increase the clearance of all enzyme substrates in a similar manner, respectively, whereas nonsynonymous coding SNPs may lead to substrate-dependent effects.

Different terms are in use for the associated pharmacokinetic phenotypes. In the case of CYP2D6 and CYP2C19, poor metabolizer (PM) refers to homozygous or compound heterozygous carriers of alleles with a complete lack of function (null allele). An efficient (or extensive) metabolizer (EM) refers to the normal phenotype, usually representing the most common phenotype mode in the population. Intermediate metabolizers (IMs) harbor either one normal or one functionally deficient allele, thus resulting in impaired drug oxidation capacity. Lastly, the UM originates from three or more functional CYP2D6 alleles or from a functionally more active CYP2C19 allele. When referring to other CYPs, these terms are not appropriate because the lack of common null alleles and the functional overlap with enzymes of similar substrate selectivity preclude the occurrence of more than two distinct phenotypic modes. In these cases, the terms slow metabolizer and rapid (normal) metabolizer are more appropriate. The CYP-specific drug oxidation phenotype can be determined in vivo by using selective model substrates (Table 4-1).

The individual polymorphisms within one gene are often linked to each other, giving rise to complex haplotype patterns and overlapping genotype-phenotype correlations. The wild type or reference haplotype was usually defined as the first historically described gene variant and therefore does not necessarily represent the most frequent allele. Individual allele frequencies may thus vary between ≪ 1% and greater than 50%. Allele frequencies of SNPs and CNVs typically vary greatly between different ethnicities.

The consequences of polymorphic drug metabolism for drug therapy need to be considered within their pharmacologic context. Loss-of-function variants will lead to reduced clearance and increased plasma concentrations of the drug itself, while gain-of-function variants will lead to increased clearance and lower plasma drug concentrations. If the drug itself is pharmacologically active and the metabolite is inactive, this should result in higher and lower drug effect and potentially drug-related toxicity due to overdosing. In the case of a prodrug, the opposite consequences are to be expected. An example for the latter is the increased formation of morphine from codeine by CYP2D6 ultrarapid metabolizers. Less clear consequences may arise if both the drug and the metabolites are pharmacologically active. An analysis of adverse drug reaction studies published between 1995 and 2000 identified 27 drugs frequently cited in connection with an adverse drug reaction. Remarkably, 59% of these 27 drugs are metabolized by at least one polymorphic enzyme, compared to only 7% of randomly selected top-selling drugs, emphasizing the clinical significance of pharmacokinetic polymorphisms.

CYP2B6 is the only functional gene of the CYP2B subfamily located on chromosome 19. In humans, CYP2B6 is a minor hepatic P450 contributing approximately 2% to 4% to the total hepatic P450 pool, but exhibits large interindividual variability of expression. This variability is in part explained by the fact that human and rodent CYP2B genes are strongly inducible by phenobarbital and other xenobiotics which act as ligands to the constitutive androstane receptor (CAR) (NR1I3) and the pregnane X receptor (PXR) (NR1I2). On ligand binding these orphan nuclear receptors dimerize with the retinoid X receptor (RXR) to bind to DNA response elements in various CYP gene promoters including CYP2B6. Ligands of these receptors include rifampicin, barbiturates, cyclophosphamide, statins, and others.

The CYP2B6 enzyme metabolizes many diverse chemicals including not only clinically used drugs but also pesticides and other environmental chemicals. Therapeutically important drugs metabolized mainly by CYP2B6 include the prodrug cyclophosphamide, which is activated by 4-hydroxylation, the non-nucleoside reverse transcriptase inhibitor efavirenz, the atypical antidepressant and smoking cessation agent bupropion, the antimalarial artemisinin, the anesthetics propofol and ketamine, and others (Table 4-1). CYP2B6 can also be reversibly or irreversibly inhibited by a variety of agents, including clopidogrel, thiotepa, ticlopidine, or voriconazole, which can lead to drug-drug interactions.