Journal article
Evidence of CYP3A Allosterism In Vivo: Analysis of Interaction Between Fluconazole and Midazolam
Clinical pharmacology and therapeutics, Vol.91(3), pp.442-449
03/2012
Handle:
https://hdl.handle.net/2376/106866
PMID: 22048224
Abstract
The allosteric effect of fluconazole (effector) on the formation of 1′–hydroxymidazolam (1′–OH–MDZ) and 4–hydroxymidazolam (4–OH–MDZ) from midazolam (MDZ), a substrate of CYP3A4/5—members of the cytochrome P450 superfamily of enzymes—was examined in healthy volunteers. Following pretreatment with fluconazole, the ratio of the areas under the curve (AUCs) for 4–OH–MDZ and MDZ (AUC4–OH/AUCMDZ) increased by 35–62%, whereas the ratio AUC1′–OH/AUCMDZ decreased by 5–37%; the ratio AUC1′–OH/AUC4–OH decreased by 46–58% after fluconazole administration and had no association with the CYP3A5 genotype. The in vitro formation of 1′–OH–MDZ was more susceptible to inhibition by fluconazole than that of 4–OH–MDZ. Fluconazole decreased the intrinsic formation–clearance ratio of 1′–OH–MDZ/4–OH–MDZ to an extent that was quantitatively comparable to in vivo observations. The elimination clearance of MDZ metabolites appeared unaffected by fluconazole. This study demonstrated that fluconazole alters formation of MDZ metabolites, both in vivo and in vitro, in a manner consistent with an allosteric interaction. The 1′–OH–MDZ/4–OH–MDZ ratio may serve as a biomarker of such interactions among MDZ, CYP3A4/5, and other putative effectors.
Clinical Pharmacology & Therapeutics (2012); 91 3, 442–449. doi:10.1038/clpt.2011.178
Metrics
6 Record Views
Details
- Title
- Evidence of CYP3A Allosterism In Vivo: Analysis of Interaction Between Fluconazole and Midazolam
- Creators
- J Yang - University of WashingtonW M Atkins - University of WashingtonN Isoherranen - University of WashingtonM F Paine - University of North Carolina at Chapel HillK E Thummel - University of Washington
- Publication Details
- Clinical pharmacology and therapeutics, Vol.91(3), pp.442-449
- Academic Unit
- Pharmaceutical Sciences, Department of
- Number of pages
- 8
- Identifiers
- 99900546565001842
- Language
- English
- Resource Type
- Journal article