Impact of Obesity on Drug Metabolism and Elimination in Adults and Children

The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N -acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.