Abstract
Drug-drug interactions (DDIs) with the HIV protease inhibitors (PIs) are complex, paradoxical (e.g., ritonavir/alprazolam), and involve multiple mechanisms. As part of a larger study to better understand these DDIs and to devise a framework for in vitro to in vivo prediction of these DDIs, we determined the inductive effect of ∼2 weeks of administration of two prototypic PIs, nelfinavir (NFV), ritonavir (RTV), and rifampin (RIF; induction positive control) on the cytochrome P450 enzymes CYP1A2, CYP2B6, CYP2C9, and CYP2D6 and the inductive or inductive plus inhibitory effect of NFV, RTV, or RIF on CYP3A and P-glycoprotein in healthy human volunteers. Statistically significant induction of CYP1A2 (2.1-, 2.9-, and 2.2-fold), CYP2B6 (1.8-, 2.4-, and 4-fold), and CYP2C9 (1.3-, 1.8-, and 2.6-fold) was observed after NFV, RTV, or RIF treatment, respectively (as expected, CYP2D6 was not induced). Moreover, we accurately predicted the in vivo induction of these enzymes by quantifying their induction by the PIs in human hepatocytes and by using RIF as an in vitro to in vivo scalar. On the basis of the modest in vivo induction of CYP1A2, CYP2B6, or CYP2C9, the in vivo paradoxical DDIs with the PIs are likely explained by mechanisms other than induction of these enzymes such as induction of other metabolic enzymes, transporters, or both.
Footnotes
This work was supported in part 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-RR00037] through 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 grant; to B.K.); a Simcyp sponsored fellowship (to B.K.); and an Achievement Rewards for College Scientists Foundation fellowship (to B.K.).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038646.
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ABBREVIATIONS:
- PI
- anti-HIV protease inhibitor
- DDI
- drug-drug interaction
- RTV
- ritonavir
- P-gp
- P-glycoprotein
- RIF
- rifampin
- NFV
- nelfinavir
- P450
- cytochrome P450
- qd
- once daily
- MTBE
- methyl t-butyl ether
- 4-OH BUP
- 4-hydroxy bupropion
- 4-OH TOLB
- 4-hydroxy tolbutamide
- DEX
- dextromethorphan
- DOR
- dextrorphan
- 3MM
- 3-methoxy morphinan
- UPLC
- ultraperformance liquid chromatography
- MS/MS
- tandem mass spectrometry
- BUP
- bupropion
- HPLC
- high-performance liquid chromatography
- AAMU
- 5-acetylamino-6-amino-3-methyluracil
- AUC
- area under the plasma concentration-time curve
- UR
- urinary ratio
- PK
- pharmacokinetic
- GMR
- geometric mean ratio
- CI
- confidence interval
- PXR
- pregnane X receptor
- CAR
- constitutive androstane receptor
- DOR/DOX
- DOR/DOX AUC ratio
- CLPO
- oral clearance
- Clform
- formation clearance
- Clrenal
- renal clearance.
- Received February 8, 2011.
- Accepted September 6, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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