Document Detail

Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans.
MedLine Citation:
PMID:  15497688     Owner:  NLM     Status:  MEDLINE    
PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.
Gondi N Kumar; Venkata K Jayanti; Marianne K Johnson; John Uchic; Samuel Thomas; Ronald D Lee; Brian A Grabowski; Hing L Sham; Dale J Kempf; Jon F Denissen; Kennan C Marsh; Eugene Sun; Stanley A Roberts
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Pharmaceutical research     Volume:  21     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-10-22     Completed Date:  2005-04-12     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1622-30     Citation Subset:  IM    
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
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MeSH Terms
Administration, Oral
Bile / metabolism
Blood Proteins / metabolism
Drug Combinations
Feces / chemistry
HIV Protease Inhibitors / administration & dosage,  pharmacokinetics*
Injections, Intravenous
Macaca fascicularis
Models, Chemical
Molecular Structure
Protein Binding
Pyrimidinones / administration & dosage,  chemistry,  pharmacokinetics*
Rats, Sprague-Dawley
Ritonavir / administration & dosage,  pharmacokinetics*
Tissue Distribution
Reg. No./Substance:
0/Blood Proteins; 0/Drug Combinations; 0/HIV Protease Inhibitors; 0/Pyrimidinones; 0/Ritonavir; 192725-17-0/lopinavir

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