Abstract
Conflicting drug-drug interaction (DDI) studies with the HIV protease inhibitors (PIs) suggest net induction or inhibition of intestinal or hepatic CYP3A. As part of a larger DDI study in healthy volunteers, we determined the effect of extended administration of two PIs, ritonavir (RTV) or nelfinavir (NFV), or the induction-positive control rifampin on intestinal and hepatic CYP3A activity as measured by midazolam (MDZ) disposition after a 14-day treatment with the PI in either staggered (MDZ ∼12 h after PI) or simultaneous (MDZ and PI coadministered) manner. Oral and intravenous MDZ areas under the plasma concentration-time curves were significantly increased by RTV or NFV and were decreased by rifampin. Irrespective of method of administration, RTV decreased net intestinal and hepatic CYP3A activity, whereas NFV decreased hepatic but not intestinal CYP3A activity. The magnitude of these DDIs was more accurately predicted using PI CYP3A inactivation parameters generated in sandwich-cultured human hepatocytes rather than human liver microsomes.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM032165]; the National Institutes of Health National Institute on Drug Abuse [Grants K24-DA00417, R01-DA14211]; the National Institutes of Health National Center for Research Resources [Grant M01-RR-00037] (to the Clinical Research Center Facility at the University of Washington); the National Institutes of Health National Institute of General Medical Sciences [Grant GM07550] (Pharmacological Sciences Training; to B.J.K.); ARCS (to B.J.K.); and Simcyp (to B.J.K.).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037523.
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ABBREVIATIONS:
- PIs
- anti-HIV protease inhibitors
- DDI
- drug-drug interaction
- RTV
- ritonavir
- HLMs
- human liver microsomes
- SCHHs
- sandwich-cultured human hepatocytes
- NFV
- nelfinavir
- MDZ
- midazolam
- RIF
- rifampin
- OH
- hydroxy
- sWEM
- supplemented Williams' E media
- AUC
- area under the plasma concentration-time curve
- IS
- internal standard
- GI
- gastrointestinal
- GMR
- geometric mean ratio.
- Received December 3, 2010.
- Accepted March 9, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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