Additional Effects On Drug Metabolism

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Enzyme Induction and Inhibition

The effect of repeated doses of a drug, or of another drug or dietary or environmental constituent on that drug, may be to enhance or inhibit the metabolism of the drug. Both enzyme induction and inhibition are important causes of drug interactions (Chapter 15). Phenobarbital is prototypical of one general type of inducer; polycyclic aromatic hydrocarbons are representative of another class that affects different CYPs. The mechanism for environmental and drug induction of CYPs involves the intermediacy of ligand-regulated transcription factors. The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are both heterodimers with the retinoid X receptor and are further described in Chapter 15. PXR and CAR are highly expressed in liver and intestine, and seem to have evolved to exhibit protective and nonspecific responses to a very wide range of exogenous compounds, as shown in Figure 11.4 (49).

Species

Different species metabolize drugs to produce varying and characteristic profiles with regard to percentages of metabolite formed in both Phase I and II reactions. This has long been recognized, but it is now known that there is considerable genetic variability in the primary structures of the CYPs and in their regulatory control through DNA- and ligand-binding domains of the PXR and CAR transcription

FIGURE 11.4 Mechanistic basis of enzyme induction resulting from drug-drug interactions. The orphan nuclear pregnane X receptor (PXR) is a transcription factor that forms a heterodimer with the nuclear retinoid X receptor (RXR) to regulate expression of the CYP3A gene. Drug A binds to PXR and induces expression of the CYP3A enzyme, thereby accelerating metabolism of drug B. (Reproduced with permission from Wilson TM, Kliewer SA. Nat Rev Drug Discov 2002;1:259-66.)

FIGURE 11.4 Mechanistic basis of enzyme induction resulting from drug-drug interactions. The orphan nuclear pregnane X receptor (PXR) is a transcription factor that forms a heterodimer with the nuclear retinoid X receptor (RXR) to regulate expression of the CYP3A gene. Drug A binds to PXR and induces expression of the CYP3A enzyme, thereby accelerating metabolism of drug B. (Reproduced with permission from Wilson TM, Kliewer SA. Nat Rev Drug Discov 2002;1:259-66.)

factor receptors. The human and rhesus PXR receptors share 100% homology in their DNA-binding domain, and 95% homology in their ligand-binding domain. In contrast, rats share 96% and 76% homology in their DNA- and ligand-binding domains, respectively. The human CAR receptor DNA-binding domain has 66% homology with the human PXR domain and there is only 45% homology in the ligand-binding domains, allowing for considerable diversity in PXR-and CAR-mediated responses to different compounds. Metabolism studies conducted in rodents, dogs, monkeys, and other species may be useful in establishing guidelines for likely drug effects in humans, but rarely can be used for predictive interspecies scaling, a topic discussed in Chapter 30.

Ruelius (50) has reviewed several examples of species differences in the metabolism of specific drugs. For example, radiolabeled ciramadol, an orally active analgesic, was administered to rats, dogs, rhesus monkeys, and humans. The interspecies comparison of the resulting urinary recovery of parent drug and metabolites in this study (Table 11.3) exemplifies the experience of investigators with other drugs.

Guengerich (51) has reviewed several studies of interspecies activities of CYP isoforms. For example, CYP1A2 has been purified and structurally characterized from rats, rabbits, mice, and humans. The different CYP1A2 isoforms catalyze most of the same biotransformations, but there are cases in which the rat and human isoforms differ in substrate activation. Considering that rat and human CYP1A2 are only 75% homologous in amino acid sequence, it is not surprising that their activities differ. Even a single amino acid mutation in rat CYP1A2 results in significant changes in catalytic activity. Further, the concentrations of CYP1A2 vary by 25-fold in humans (10-245 pmol/mg protein) and differ from those in the rat (4-35 pmol/mg protein in untreated vs 830-1600 pmol/mg protein in polychlorinated biphenyl treated). Monkeys lack CYP1A2, a critical issue in the choice of this animal for cancer bioas-says. Interspecies variation in the CYP3A subfamilies provides an especially important example because CYP3A4 is involved in the oxidation of 59% of the drugs used today. Humans express CYPs 3A4, 3A5, and 3A7 (the latter in fetal tissue and placenta); rats express CYPs 3A1, 3A2, 3A9, 3A18, and 3A6; rabbits express only CYP3A6. Such genetically determined enzyme differences are reflected in other drug-metabolizing enzymes and in their responses to inducers and inhibitors, further complicating extrapolation of drug metabolism between species.

The effects of sex on drug disposition and phar-macokinetics have been incompletely evaluated but may be significant. In addition, the contribution of sex differences is sometimes difficult to separate from the major complicating effects of dietary and environmental inducers and inhibitors on drug-metabolizing enzymes. Sex differences in drug metabolism are considered in detail in Chapter 21.

The effects of age on drug metabolism are discussed in specific chapters dealing with pediatric (Chapter 23) and geriatric (Chapter 24) clinical pharmacology. The most significant age differences are expressed developmentally in that drug-metabolizing enzyme systems frequently are immature in neonates. An important example of this is provided by UDP-glucuronosyltransferase. Particularly in premature infants, hepatic UDP-glucuronosyltransferase activity is markedly decreased and does not reach adult levels until 14 weeks after birth (52). This results in increased serum levels of unconjugated bilirubin and a greater risk of potentially fatal kernicterus, which is likely when the serum bilirubin levels exceed 30 mg/dL. Low conjugation capacity can be exacerbated by

TABLE 11.3 Renal Elimination of Ciramidol and Its Major Metabolites following a Single Oral Dose of

[14C]Ciramidolfl

Percentage of dose in urine

TABLE 11.3 Renal Elimination of Ciramidol and Its Major Metabolites following a Single Oral Dose of

[14C]Ciramidolfl

Percentage of dose in urine

Species

Total radioactivity

Unchanged ciramidol

Aryl-O-glucuronide

Alicyclic-O-glucuronide

Rat

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