Effect of psychotropic medication on the in vitro metabolism of buprenorphine in human cDNA-expressed cytochrome P450 enzymes.
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(50) values without preincubation were higher than those after 30-min preincubation, with zolpidem 113.1 microM and midazolam 20.25 microM. Following a 30-min preincubation period in the absence of the probe substrate BUP, the apparent IC(50) values for zolpidem and midazolam were 20.17 microM and 3.5 microM.


CONCLUSIONS
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.
Bomsien
Stephanie
S
Institute of Legal Medicine and Traffic Medicine, Ruprecht-Karls University, Heidelberg, Germany. stephanie_wenzel@med.uni-heidelberg.de
Aderjan
Rolf
R
Mattern
Rainer
R
Skopp
Gisela
G
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002047:Buprenorphine / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008874:Midazolam / Q000494:pharmacology*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D000077334:Zolpidem
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011619:Psychotropic Drugs; D011725:Pyridines; D002047:Buprenorphine; D000077334:Zolpidem; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam