Effect of lipophilicity on drug distribution and elimination: Influence of obesity
Effect of lipophilicity on drug distribution and elimination: Influence of obesity
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DOI：
10.1111/bcp.14735
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发表时间：
2021-02-16
影响因子：
3.4
通讯作者：
Greenblatt, David J.
中科院分区：
文献类型：
--
作者：
Bruno, Christopher D.;Harmatz, Jerold S.;Greenblatt, David J.
目的 对于给定的被动分布的亲脂性药物，肥胖个体体内分布的程度（药代动力学分布容积，V-d）随着肥胖程度的增加而增加。本研究的目的是评估一系列药物与体外亲脂性相关的药物分布，以及与肥胖相关的 V-d 相对增加。 方法 正常体重对照和肥胖受试者队列接受单剂量药物，范围从亲水性（对乙酰氨基酚、水杨酸盐）到亲脂性（丙咪嗪、维拉帕米）。脂质溶解度通过高压液相色谱 (HPLC) 保留指数 (Log(10)(HPLC)) 和辛醇-水分配系数 (LogP) 的对数转换值来测量。结果 在正常体重对照中，蛋白质结合归一化的 V-d 与 Log(10)(HPLC) (R-2 = .65) 和 LogP (R-2 = .78) 高度相关。在肥胖组中，所有药物的 V-d 均增加，但随着脂溶性的增加，个别药物的相对增加（与对照组相比）不成比例地增加。由于清除率与亲脂性无关，因此增加的 V-d 会导致肥胖队列中的消除半衰期不成比例地平行增加，这与 Log(10)(HPLC) (R-2 = .62) 相关。结论 亲脂性是体内 V-d 以及肥胖患者药物 V-d 增加的主要相关因素。由此导致的肥胖半衰期延长，在长期用药期间和之后延迟药物积累和清除方面具有临床安全性意义。对于给定药物，这种作用的大小和重要性取决于肥胖程度以及特定药物的脂溶性。
Aims For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, V-d) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in V-d associated with obesity across a series of drugs.Methods Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil). Lipid solubility was measured by the log-transformed values of the high-pressure liquid chromatographic (HPLC) retention index (Log(10)(HPLC)), and the octanol-water partition coefficient (LogP).Results Among normal-weight controls, V-d normalized for protein binding was highly correlated with Log(10)(HPLC) (R-2 = .65) and with LogP (R-2 = .78). V-d of all drugs was increased in the obese cohort, but the relative increase (compared to controls) for individual drugs was disproportionately greater as lipid solubility increased. Since clearance was unrelated to lipophilicity, the increased V-d produced a parallel disproportionate increase in elimination half-life in the obese cohort that was associated with Log(10)(HPLC) (R-2 = .62).Conclusion Lipophilicity is a principal correlate of in vivo V-d, as well as the increased V-d of drugs in obese patients. The consequent prolongation of half-life in obesity has clinical safety implications in terms of delayed drug accumulation and washout during and after chronic dosage. The magnitude and importance of this effect for a given drug depends on the degree of obesity, as well as the lipid-solubility of the specific drug.