CYP3A4-mediated lopinavir bioactivation and its inhibition by ritonavir.

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Li F, Lu J, Ma X

CYP3A4-mediated lopinavir bioactivation and its inhibition by ritonavir.

Drug Metab Dispos. 2012 Jan;40(1):18-24. doi: 10.1124/dmd.111.041400. Epub 2011 Sep 27.

PubMed ID

21953914 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drugs

Lopinavir

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Lopinavir	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Lopinavir	Cytochrome P450 2D6	Protein	Humans	Unknown	Substrate	Details
Lopinavir	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details

Drug Interactions

Drugs	Interaction
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Lopinavir Ketoconazole	The serum concentration of Lopinavir can be increased when it is combined with Ketoconazole.