Intersubject variation in the pharmacokinetics of chlorpromazine in healthy men

Interpatient variation in response to therapy with antipsychotic drugs is a major problem. This study was designed to assess the extent of variation in disease-free subjects in whom known sources of variance were controlled as much as possible. The subjects were 32 healthy, nonsmoking males of European origin, aged 18-25 years, and weighing no more than +/- 15% from the ideal weight for height. After an overnight fast, each subject ingested 50 mg of chlorpromazine. Plasma samples were harvested over a 24-hour period during which the subjects were on a standardized, caffeine-free diet. Plasma levels of chlorpromazine were measured by gas-liquid chromatography-mass spectrometry. The results showed wide intersubject variation in all pharmacokinetic parameters including maximum concentration, area under the curve, and oral clearance. Furthermore, none of the data were normally distributed. For each pharmacokinetic parameter, the distribution was leptokurtotic and skewed. As a consequence, the geometric means provided better estimates of central tendency than the arithmetic means. It seems that a major proportion of intersubject variation is an inherent problem that cannot be accounted for by differences in race, diet, smoking habits, or concomitant drug ingestion.