Effects of obesity on the cytochrome P450 enzyme system

Objective: This review evaluates the effect of obesity on the various isozy mes of the cytochrome P450 enzyme system. Materials and method: A Medline s earch of the international literature on drug metabolism and obesity from 1 966 to early 1998 was conducted. All English language studies in humans tha t compared the pharmacokinetics of a given medication between obese and non -obese subjects were evaluated. Any study in which the substrate examined i s excreted unchanged, not metabolized primarily by a single cytochrome P450 isozyme or which is considered a high extraction compound was excluded fro m this review. Results: Despite the prevalence of obesity, the known health consequences of obesity and the increase of medication usage in the obese population, very few studies have attempted to establish the effect of this condition on the cytochrome P450 enzyme system. Numerous studies, however, have compared pharmacokinetic parameters between obese and nonobese subjec ts for individual drugs. By examining those trials in which the agents stud ied all undergo biotransformation via the same CYP450 isozyme, a preliminar y appreciation of the effect of obesity on the activity of that particular isozyme can be attained. Conclusions: The effect of obesity on CYP450 appea rs to be isozyme-specific with the activity of cytochrome P450 3A4 decreasi ng and that of cytochrome P450 2E1 increasing. The effect of obesity on the cytochrome P450 1A2, 2C9, 2C19, and 2D6 isozymes is inconclusive.