Alterations in drug distribution and clearance due to obesity

D. R. Abernethy, D. J. Greenblatt, M. Divoll, J. S. Harmatz, R. I. Shader

Research output: Contribution to journalArticle

Abstract

The influence of obesity on drug disposition was assessed using antipyrine (distribution limited mainly to body water) and diazepam (extensively distributed in fat) as model compounds. Pharmacokinetic parameters were determined after single i.v. doses administered to obese subjects and to controls of normal weight matched for age and sex. Antipyrine elimination half-life (T 1/2 β) in obese subjects (mean: 15.0 hr) was longer (P<.005) than in controls (10.7 hr) due to trends toward larger volume of distribution (Vd) (44.9 vs. 39.7 liters) and decreased clearance (38.0 vs. 47.6 ml/min). Diazepam T 1/2 β in obese subjects (95.0 hr) was greatly prolonged in comparison to controls (40.0 hr, P<.001), but this was due entirely to a large increase in Vd in the obese (292 liters) as compared to controls (91 liters, P<.001). Among all antipyrine recipients (23 obese and 25 control), Vd corrected for ideal body weight (IBW) increased linearly with percentage of IBW (r=0.68, P<.001). The slope of the regression line indicated that antipyrine distributes only into 30% of body weight in excess of IBW. Among all diazepam recipients, Vd/IBW also increased linearly with percentage of IBW (r=0.88, P<.001), but the slope indicated disproportionate (5-fold) distribution into weight in excess of IBW. Among 25 subjects who received both drugs, T 1/2 β for antipyrine and diazepam were highly correlated (r=0.68, P<.002), but clearance was not (r=0.01). Instead, Vd for the two drugs was positively correlated (r=0.48, P<.01), partly explaining the correlation of T 1/2 β. Thus, these findings suggest that the effect of obesity on drug distribution is strongly dependent on the physiochemical properties of the drug. Changes in T 1/2 β among obese individuals may reflect alterations in drug distribution rather than clearance.

Original languageEnglish (US)
Pages (from-to)681-685
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume217
Issue number3
StatePublished - Sep 21 1981

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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  • Cite this

    Abernethy, D. R., Greenblatt, D. J., Divoll, M., Harmatz, J. S., & Shader, R. I. (1981). Alterations in drug distribution and clearance due to obesity. Journal of Pharmacology and Experimental Therapeutics, 217(3), 681-685.