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Effect of psychotropic medication on the in vitro metabolism of buprenorphine in human cDNA-expressed cytochrome P450 enzymes

European Journal of Clinical Pharmacology, ISSN: 0031-6970, Vol: 62, Issue: 8, Page: 639-643
2006
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Objective: The aim of the present study was to estimate the drug interaction potential of psychtropic medication on buprenorphine (BUP) N-dealkylation using cDNA-expressed cytochrome P450 (CYP) enzymes. Methods: BUP was incubated with psychotropic drugs and cDNA-expressed CYP 3A4 and CYP 2C8 enzymes. Seven substances were screened for their inhibition potency. To check for a mechanism-based component in inhibition, all substances were tested with and without preincubation, respectively. Norbuprenorphine (NBUP) concentrations were determined by liquid chromatography/tandem mass spectrometry, following liquid/liquid extraction. Results: Midazolam and zolpidem demonstrated greatest inhibition in screening experiments. As expected, IC values without preincubation were higher than those after 30-min preincubation, with zolpidem 113.1 μM and midazolam 20.25 μM. Following a 30-min preincubation period in the absence of the probe substrate BUP, the apparent IC values for zolpidem and midazolam were 20.17 μM and 3.5 μM. Conclusion: Both midazolam and zolpidem showed a distinct inhibitory potency towards NBUP formation by CYP 3A4, implicating a decreased conversion of BUP. When preincubated, the inhibitory potency was increased, which strongly suggests a metabolically activated component in inhibition. © Springer-Verlag 2006.

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