Effect of lipophilicity on drug distribution and elimination: Influence of obesity

• Published in: British journal of clinical pharmacology 2021-08, Vol.87 (8), p.3197-3205
• Main Authors: Bruno, Christopher D., Harmatz, Jerold S., Duan, Su X., Zhang, Qingchen, Chow, Christina R., Greenblatt, David J.
• Format: Article
• Language: English
• Subjects: elimination half‐life; lipid solubility; obesity; pharmacokinetics; volume of distribution
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.14735

Aims For a given passively‐distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, Vd) 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 Vd 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 (Log10(HPLC)), and the octanol–water partition coefficient (LogP). Results Among normal‐weight controls, Vd normalized for protein binding was highly correlated with Log10(HPLC) (R2 = .65) and with LogP (R2 = .78). Vd 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 Vd produced a parallel disproportionate increase in elimination half‐life in the obese cohort that was associated with Log10(HPLC) (R2 = .62). Conclusion Lipophilicity is a principal correlate of in vivo Vd, as well as the increased Vd 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.