Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans.
OBJECTIVE
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.
Kumar
Gondi N
GN
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Jayanti
Venkata K
VK
Johnson
Marianne K
MK
Uchic
John
J
Thomas
Samuel
S
Lee
Ronald D
RD
Grabowski
Brian A
BA
Sham
Hing L
HL
Kempf
Dale J
DJ
Denissen
Jon F
JF
Marsh
Kennan C
KC
Sun
Eugene
E
Roberts
Stanley A
SA
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004338:Drug Combinations; D005243:Feces / Q000737:chemistry; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D061466:Lopinavir; D008252:Macaca fascicularis; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D001798:Blood Proteins; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir