PT  - JOURNAL ARTICLE
AU  - Feng Li
AU  - Jie Lu
AU  - Xiaochao Ma
TI  - CPY3A4-Mediated Lopinavir Bioactivation and Its Inhibition by Ritonavir
AID  - 10.1124/dmd.111.041400
DP  - 2012 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 18--24
VI  - 40
IP  - 1
4099  - http://dmd.aspetjournals.org/content/40/1/18.short
4100  - http://dmd.aspetjournals.org/content/40/1/18.full
SO  - Drug Metab Dispos2012 Jan 01; 40
AB  - The combination of lopinavir (LPV) and ritonavir (RTV) is one of the preferred regimens for the treatment of HIV infection with confirmed efficacy and relatively low toxicity. LPV alone suffers the poor bioavailability due to its rapid and extensive metabolism. RTV boosts the plasma concentration of LPV by suppressing its metabolism and thus increasing LPV efficacy. In the current study, we found that RTV also inhibits LPV bioactivation. LPV bioactivation was investigated in human liver microsomes and cDNA-expressed human cytochromes P450. Twelve GSH-trapped reactive metabolites of LPV were identified by using a metabolomic approach. Semicarbazide-trapped reactive metabolites of LPV were also detected. RTV effectively suppressed all pathways of LPV bioactivation via CYP3A4 inhibition. Our data together with previous reports suggest that LPV plus RTV is an ideal combination because RTV not only boosts LPV plasma concentration, but it decreases LPV bioactivation.