METABOLISM OF BENZODIAZEPINES AND POTENTIAL FOR DRUG-DRUG INTERACTIONS WITH CANNABINOIDS

Keti Bardhi

doi:10.7273/000006914

Temazepam and oxazepam are commonly prescribed 3-hydroxyybenzodiazepines known for their hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. Oxazepam is glucuronidated in an enantiomeric-specific manner, with S-oxazepam metabolized predominantly by UDP-glucuronosyltransferase (UGT) 2B15 (minor contribution of UGT2B7) and R-oxazepam glucuronidated by 1A9 and 2B7. Temazepam undergoes phase II metabolism by UGT enzymes; however, a comprehensive analysis of all the UGT isoforms involved in temazepam metabolism had not previously been performed. Benzodiazepines are commonly used and misused in combination with other illicit drugs, including cannabis, which is also utilized to treat anxiety, insomnia, pain, and seizures. Previous in vitro studies utilizing probe substrates indicate that major cannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit the major UGT enzymes. To determine the specific isoforms involved in the metabolism of temazepam enantiomers, reaction phenotyping, enzyme kinetics, and chemical inhibition studies were performed. Reaction phenotyping studies showed that UGTs 1A3, 1A9, 2B4, 2B7, and 2B17 are involved in both R- and S-temazepam glucuronidation, while UGTs 1A6 and 2B15 selectively metabolize S-temazepam. Kinetic studies using recombinant UGTs demonstrated that UGTs 2B7 and 1A9 displayed the highest intrinsic clearance (CLin) for R-temazepam glucuronidation, while 1A6 and 2B15 exhibited the highest CLin for S-temazepam glucuronidation, suggesting enantioselective glucuronidation of temazepam. Chemical imbibition studies showed that fluconazole (a UGT2B7 selective inhibitor) inhibited R-temazepam glucuronidation, while serotonin and amitriptyline (non-selective substrate of UGT1A6 and inhibitor of UGT2B15, respectively) inhibited S-temazepam glucuronidation, indicating major contributions of these three enzymes in racemic temazepam metabolism. Considering the involvement of other enzymes, S-temazepam may not be an optimal probe substrate for UGT2B15. In addition, to determine the potential inhibitory effects of cannabinoids and their major circulating metabolites [11-hydroxy-Δ9-tetrahydrocannabiol (11-OH-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-COOH-CBD)] on UGT-mediated metabolism of oxazepam and temazepam, in vitro studies (inhibition screenings, and IC50,u and Ki,u determinations) and in vitro to in vivo extrapolation were performed. CBD, 11-OH-THC, and THC exhibited stronger inhibition of R-oxazepam glucuronidation, with Ki,u values 2-to-5-fold lower as compared to those observed for S-oxazepam glucuronidation. A similar pattern of inhibition was observed from the preliminary screening studies with temazepam, where CBD and 7-OH-CBD strongly inhibited R-temazepam glucuronidation. Mechanistic static modeling showed a potential for clinically significant interaction between oxazepam and oral CBD and THC (AUCR > 1.25). Together, these findings demonstrate that major cannabinoids and their metabolites inhibit the UGT enzymes responsible for oxazepam metabolism, and that UGTs 1A6, 2B7, and 2B15 are the main enzymes involved in temazepam glucuronidation, and that concomitant use with substrates, inhibitors, or inducers of these enzymes can lead to drug-drug interactions.

METABOLISM OF BENZODIAZEPINES AND POTENTIAL FOR DRUG-DRUG INTERACTIONS WITH CANNABINOIDS

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