Cheymol G
Service de Pharmacologie, C.H.U. Saint-Antoine, Paris, France.
Fundam Clin Pharmacol. 1988;2(3):239-56. doi: 10.1111/j.1472-8206.1988.tb00635.x.
In the obese, modifications in body constitution (higher percentage of fat and lower percentage of lean tissue and water) can affect drug distribution in the tissues. For slightly liposoluble molecules (e.g., digoxin, antipyrine), the equilibrium distribution volume (V), total and per kilogram weight, is significantly less than that of control subjects. With lipophilic drugs (e.g., barbiturates, benzodiazepines), this parameter is significantly increased, explaining the prolongation of the plasma elimination half-life. For drugs that are almost equally soluble in water and oil (methyl xanthines, aminoglycosides), the V is slightly increased in the obese. The other main factors involved in drug diffusion in the tissues are binding to plasma and tissue proteins, and regional blood flow. In the obese the binding of drugs to albumin does not seem to be altered. A marked increase in plasma alpha-glycoprotein acid and in propranolol binding has been reported in some studies; this has not been corroborated by other authors. Although the cardiac output and total blood volume are increased in the obese, the blood flow per gram of fat is less than in nonobese subjects. This could limit diffusion in the tissues of some lipophilic drugs. Studies on hepatic clearance of drugs are not available in the obese, but hepatic histological alterations have been described. In most publications concerning drugs with biotransformation as the principal elimination route, the total plasma clearance is not reduced. Up to the present, there are no reports of any impairment involving renal elimination of drugs in the obese. Dose-adjustment of hydrophilic drugs is assessed according to the ideal weight of the individual obese subject; with lipophilic drugs the loading dose can be fixed according to the total weight; calculation of the maintenance dose depends on possible changes in the total clearance.
在肥胖者中，身体构成的改变（脂肪百分比更高，瘦组织和水的百分比更低）会影响药物在组织中的分布。对于轻度脂溶性分子（如地高辛、安替比林），每千克体重的平衡分布容积（V）显著低于对照组。对于亲脂性药物（如巴比妥类、苯二氮䓬类），该参数显著增加，这解释了血浆消除半衰期的延长。对于在水和油中溶解度几乎相同的药物（甲基黄嘌呤、氨基糖苷类），肥胖者的V略有增加。药物在组织中扩散的其他主要因素包括与血浆和组织蛋白的结合以及局部血流。在肥胖者中，药物与白蛋白的结合似乎没有改变。一些研究报道血浆α-糖蛋白酸和普萘洛尔结合显著增加；但其他作者并未证实这一点。虽然肥胖者的心输出量和总血容量增加，但每克脂肪的血流量低于非肥胖者。这可能会限制一些亲脂性药物在组织中的扩散。目前尚无关于肥胖者药物肝清除率的研究，但已描述了肝脏组织学改变。在大多数关于以生物转化为主要消除途径的药物的出版物中，总血浆清除率并未降低。到目前为止，尚无关于肥胖者药物肾排泄受损的报道。亲水性药物的剂量调整根据肥胖个体的理想体重进行评估；对于亲脂性药物，负荷剂量可根据总体重确定；维持剂量的计算取决于总清除率可能的变化。
