Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans

Pharm Res. 2004 Sep;21(9):1622-30. doi: 10.1023/b:pham.0000041457.64638.8d.


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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Bile / metabolism
  • Blood Proteins / metabolism
  • Dogs
  • Drug Combinations
  • Feces / chemistry
  • Female
  • HIV Protease Inhibitors / administration & dosage
  • HIV Protease Inhibitors / pharmacokinetics*
  • Humans
  • Injections, Intravenous
  • Lopinavir
  • Macaca fascicularis
  • Male
  • Models, Chemical
  • Molecular Structure
  • Protein Binding
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Ritonavir / administration & dosage
  • Ritonavir / pharmacokinetics*
  • Tissue Distribution


  • Blood Proteins
  • Drug Combinations
  • HIV Protease Inhibitors
  • Pyrimidinones
  • Lopinavir
  • Ritonavir