Affecting Drug Metabolism

As described in Chapter Ih drug metabolism is composed of two distinct pathways of biochemical processing/ Phase I and Phase II. Phase I is a chemical modification (typically oxidatioiy hydrolysis/ or reduction reactions) performed primarily by members of the CYP enzyme family (49). Phase II metabolism consists of the biotransformation 

TABLE 15.1 Selected Cytochrome P450 Substrates/ Inhibitors/ and Inducers 

In reversible inhibition, enzymatic activity is regained by the systemic elimination of inhibitor/ such that the time to enzyme recovery is dependent on the elimination half-life of the inhibitor. Competitive inhibition is characterized by competition between substrate and inhibitor for the enzyme s active site. Competition for enzyme binding can be overcome by increasing the concentration of substrate/ thereby sustaining the 

FIGURE 15.1 Theoretical plasma concentration-time profiles of a drug in the presence of a CYP eiazyme indncer (dashed line) and inhibitor (solid line). 

Irreversible or quasi-irreversible metabolic inhibition occurs when either the parent compound or a metabolic intermediate binds to the reduced ferrous heme portion of the P450 enzyme/ thereby inactivating it (51). In irreversible inhibition, or suicide inhibition/ the intermediate forms a covalent bond with the CYP protein or its heme component/ causing permanent 

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Their activities may be altered in diseased tissues (eg, cirrhosis), affecting drug metabolism Genotyping the P450 profile of patients (eg, to detect polymorphisms) may in the future permit individualization of drug therapy... 

Extrapolation of the result to the patient population (especially children or patients with hepatic or renal diseases affecting drug metabolism)... 

Factors that affect drug metabolism will influence the development of serious adverse effects. TPMT, one of the three enzymes that metabolize 6-MP, is encoded by a gene on chromosome 6 that contains functional polymorphisms. Multiple variants have been described ( 2, 3A, 3B, 3C, 3D, 4, 5, 6, 7, 10 31,32) that result in lower TPMT activity, leading to preferential metabolism of 6-MP by the HGPRT enzyme. This results in an increase in the amount of cytotoxic thioguanine nucleotides and greater myelotoxicity. There appears to be an allele dose-dependent... 

Caution Recommended doses do not apply for adult patients with body weight less than 50 kg. Recommended doses do not apply to patients with renal or hepatic insufficiency or other conditions affecting drug metabolism and kinetics. Starting doses should be lower for elderly patients. 

The apparent variable effect of age on drug metabolism is probably due to the fact that age is only one of many factors that affect drug metabolism. For example, cigarette smoking, alcohol intake, dietary modification, drugs, viral illness, caffeine intake, and other unknown factors also affect the rate of drug metabolism. 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

Introduced mutations affecting drug metabolism allow the study of drug metabolism, biotransformation and eventual undesired toxic side effects. 

The nutritional status of an animal is well recognized as having an important influence on drug metabolism, disposition, and toxicity. The lack of various nutrients may affect drug metabolism, though not always causing a depression of metabolic activity. Lack of protein has been particularly well studied in this respect and shows a marked influence on drug metabolism. 

A few of the factors shown in the outer circle of Fig. 1 have not been studied in human subjects. Those have been demonstrated in laboratory animals to affect drug metabolism and disposition. 

Kalow W, Bertilsson L. Interethnic factors affecting drug metabolism. Adv Drug Res 1994 25 1-53. 

Famotidine is a histamine H2 receptor antagonist. It does not affect drug metabolism and it has been claimed to be free of the antiandrogenic effect of cimetidine however in one woman who accidentally took double doses of the drug for some months it did cause hyperprolactinemia and breast engorgement (SEDA-18, 372). In other ways it bears a very close resemblance to cimetidine for example, headache and confusion with intravenous use are reported, as are thrombocytopenia and pancytopenia (SEDA-15, 395). 

A retrospective study in 22 children with cancers addressed the potential interaction between fluconazole and cyclophosphamide. Children with an established profile of cyclophosphamide metabolism who were not receiving other drugs known to affect drug metabolism were selected 9 were taking fluconazole and 13 were controls. The plasma clearance was significantly lower in patients taking concomitant fluconazole (2.4 versus 4.2 1/ hour/m ). It is unclear whether this interaction is associated with a reduction in the therapeutic efficacy of cyclophosphamide. 

The nutritional status of an animal is well recognized as having an important influence on drug metabolism, disposition and toxicity. The lack of various nutrients may affect drug metabolism, though not always causing a depression of metabolic activity. Lack of protein has been particularly well studied in this respect, and shows a marked influence on drug metabolism. Thus, rats fed on low-protein diets (5%) show a marked loss of microsomal enzyme activity when compared with those animals fed a 20% protein diet (table 5,17). The decline in activity is accompanied by a decline in the level of liver microsomal protein. Both cytochrome P-450 content and cytochrome P-450 reductase activity are reduced by a 5% protein diet. 

Gillette, J. R. (1971). Factors affecting drug metabolism. Annals of the New York Academy of Sciences, 179, 43—66. 

Caution Recommended doses do not apply to patients widi renal or hepatic insufficiency or odier conditions affecting drug metabolism and kinetics. 

Gibson GG, Skett P. Factors affecting drug metabolism internal factorsin . Introduction to Drug Metabolism. London Blackie Academic and Professional, 1994 107-132. 

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