Abernethy D R, Greenblatt D J
Clin Pharmacokinet. 1986 May-Jun;11(3):199-213. doi: 10.2165/00003088-198611030-00002.
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 alpha 1-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.(ABSTRACT TRUNCATED AT 400 WORDS)
目前已对许多药物在肥胖个体中的处置情况进行了研究，并可得出一些一般性结论。迄今为止评估的药物吸收情况不会因肥胖而改变。某些药物（包括大多数苯二氮䓬类药物、硫喷妥钠、苯妥英、维拉帕米和利多卡因）的表观分布容积大幅增加。已注意到甲基黄嘌呤、氨基糖苷类药物、万古霉素、布洛芬、泼尼松龙和肝素的分布容积有适度增加。肥胖状态下，地高辛、西咪替丁和普鲁卡因胺的分布情况未发生改变。目前尚不清楚肥胖状态下某些药物分布增加而其他药物分布不变的机制。这可能部分归因于药物分子的亲脂性；然而，其他复杂且尚未完全理解的因素也导致肥胖患者药物分布的变异性。肥胖状态下，与白蛋白结合的药物的蛋白结合情况不会发生显著变化。相比之下，一些研究报告称，与α1 - 酸性糖蛋白（AAG）结合的药物可能会因血清AAG浓度升高而增加结合；然而，这并非一致的发现。除布洛芬和泼尼松龙外，肥胖状态下药物的氧化生物转化变化极小，布洛芬和泼尼松龙的清除率会随着体重的高度相关函数而增加。肥胖状态下，药物结合作用会随着体重增加而一致增加，对乙酰氨基酚、劳拉西泮和奥沙西泮已进行了相关研究。肥胖状态下药物乙酰化情况可能不变，目前仅对普鲁卡因胺进行了评估。与正常体重对照相比，包括利多卡因、维拉帕米和咪达唑仑在内的高清除率药物在肥胖个体中的清除率没有变化。对于某些评估的药物（地高辛、西咪替丁），药物的肾清除率变化不大，而其他药物（氨基糖苷类药物、未代谢的普鲁卡因胺）的肾清除率则会增加。目前正在对合适的肥胖动物模型进行表征，以阐明肥胖人群体内这些药代动力学观察结果的机制。两种模型，即Zucker肥胖大鼠和肥胖的自助饮食喂养的雄性Sprague - Dawley大鼠，已提供了有关茶碱、苯巴比妥和维拉帕米评估的初步生理药代动力学数据。（摘要截选至400字）
