Clinical pharmacokinetics of drugs in obesity. An update.

Obesity is common enough to constitute a serious medical and public health problem. Drug prescription for obese patients is difficult since dosages based on pharmacokinetic data obtained in normal-weight individuals could induce errors. In obese patients, physiopathological modifications are likely to affect drug tissue distribution and elimination. Body constitution is characterised by a higher percentage of fat and a lower percentage of lean tissue and water. Although the cardiac output and total blood volume are increased, the blood flow per gram of fat is less than in nonobese individuals. Histological hepatic alterations are commonly reported in morbidly obese individuals. A higher glomerular filtration rate is also observed. Most of the pharmacokinetic information concerning obesity deals with distribution. Published data concerning molecules with moderate and weak lipophilicity are homogeneous. In obese compared with normal weight individuals, the total volume of distribution (Vd) is moderately increased (aminoglycosides, caffeine) or similar (H2-blockers, neuromuscular blockers), but the Vd corrected by kilogram of actual bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight. For highly lipophilic drugs, despite this common characteristic, discrepancies in distribution in obesity exist between drugs belonging to different pharmacological classes. Some drugs show a clear augmentation of Vd and elimination half-life (benzodiazepines, carbamazepine, trazodone, verapamil, sufentanil), indicating a marked distribution into adipose tissue. For others, Vd and Vd/kg are decreased (cyclosporin, propranolol), suggesting that factors other than lipid solubility intervene in tissue distribution. As a general trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, and also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Usually CL is identical in obese and nonobese individuals, sometimes it is increased in obesity (enflurane, halothane, prednisolone, some benzodiazepines). With some drugs a significant reduction in CL is observed in obese individuals (methylprednisolone, propranolol). Renal clearance of aminoglycosides and cimetidine increases in obese individuals. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in CL. In some cases (atracurium, prednisolone) dosage adjustment does not follow these recommendations, owing to pharmacodynamic data.