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.
Footnotes
This work was supported by the National Institutes of Health National Center for Research Resources [Grant COBRE 5P20-RR021940].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- LPV
- lopinavir
- RTV
- ritonavir
- PI
- protease inhibitor
- LPV/r
- ritonavir-boosted lopinavir regimen
- DMP
- 2,6-dimethylphenol
- HLM
- human liver microsomes
- PBS
- phosphate-buffered saline
- OPLS-DA
- orthogonal projection to latent structures-discriminant analysis
- TOFMS
- time-of-flight mass spectrometry
- UPLC
- ultraperformance liquid chromatography
- P450
- cytochrome P450
- rcf
- relative centrifugal force
- MS/MS
- tandem mass spectrometry.
- Received June 27, 2011.
- Accepted September 27, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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