Effects of obesity on the cytochrome P450 enzyme system

Objective: This review evaluates the effect of obesity on the various isozymes of the cytochrome P450 enzyme system. Materials and method: A Medline search of the international literature on drug metabolism and obesity from 1966 to early 1998 was conducted. All English language studies in humans that compared the pharmacokinetics of a given medication between obese and non-obese subjects were evaluated. Any study in which the substrate examined is excreted unchanged, not metabolized primarily by a single cytochrome P450 isozyme or which is considered a high extraction compound was excluded from 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 non-obese subjects for individual drugs. By examining those trials in which the agents studied all undergo biotransformation via the same CYP450 isozyme, a preliminary appreciation of the effect of obesity on the activity of that particular isozyme can be attained. Conclusions: The effect of obesity on CYP450 appears to be isozyme-specific with the activity of cytochrome P450 3A4 decreasing and that of cytochrome P450 2E1 increasing. The effect of obesity on the cytochrome P450 1A2, 2C9, 2C19, and 2D6 isozymes is inconclusive.