Drug Disposition in Obese Humans: An Update

Drug disposition for many drugs has now been studied in obese individuals and some general conclusions can be drawn. Absorption of drugs evaluated to date is unchanged due to obesity. Apparent volume of distribution is greatly increased for some drugs including most benzodiazepines, thiopentone, phenytoin, verapamil and lignocaine (lidocaine). Modest increases in volume of distribution have been noted for methylxanthines, aminoglycosides, vancomycin, ibuprofen, prednisolone and heparin. Distribution of digoxin, cimetidine and procainamide is unchanged in obesity. The mechanism for the increased distribution of some drugs and unchanged distribution of others in obesity is unclear at present. It may be in part due to the lipophilic character of the drug molecule; however, other complex and as yet poorly understood factors contribute to the variability in drug distribution in obese patients. Protein binding of drugs bound to albumin is not dramatically changed in obesity. In contrast, some studies report that drugs bound to α₁-acid glycoprotein (AAG) may have increased binding that is related to increased serum AAG concentration; however, this is not a consistent finding. Oxidative drug biotransformation is minimally changed in obesity with the exceptions of ibuprofen and prednisolone, for which clearance increases as a highly correlated function of total bodyweight. Drug conjugation uniformly increases as a function of bodyweight in obesity, with paracetamol (acetaminophen), lorazepam and oxazepam having been studied. Drug acetylation may be unchanged in obesity, with only procainamide evaluated at this time. High clearance drugs, including lignocaine, verapamil and midazolam, have no change in clearance in obese individuals compared to normal bodyweight controls. Renal clearance of drugs is little changed for some drugs evaluated (digoxin, cimetidine), and increased for others (aminoglycosides, unmetabolised procainamide). Characterisation of appropriate animal models of obesity is underway to clarify the mechanisms for these in vivo pharmacokinetic observations in obese man. Two models, the Zucker obese and the obese cafeteria-fed male Sprague-Dawley rat, have provided preliminary physiological pharmacokinetic data with evaluations of theophylline, phenobarbitone and verapamil. The Zucker genetically obese rat may be somewhat limited as a model due to impairment in renal function and impairment in capacity for regulation of cytochrome P-450 activity in obese animals that differs from heterozygous lean Zucker rats. Limitations of the cafeteria-fed Sprague-Dawley rat model of obesity identified to date are that only male rats will eat to a significant extent of obesity, the alteration in animal diet required to achieve obesity is difficult to properly control in pharmacokinetic studies in which dietary alteration in man and animals is well known to change oxidative drug clearance, and that at least 3 months of feeding the specialised diet are required to achieve bodyweight at least 40% in excess of control animals. With further identification and understanding of the limitations of these models, a mechanistic understanding of pharmacokinetic alterations associated with human obesity may be forthcoming.