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Author: David E. Moody

Abstract:

This is a progress report on a project that is testing the hypothesis that inhibition of in vitro drug metabolism can predict potential drug interactions with the opioids buprenorphine, methadone, and oxycodone.

The overall assessment is that substantial progress has been made in meeting project objectives. Researchers have optimized incubation conditions for buprenorphine, methadone, and oxycodone in human liver microsomes (HLM) and with the relevant DNA-expressed cytochrome P450s (rCYPs) (i.e., CYP3A4 for all three substrates, 2C8 for buprenorphine, 2B6 for methadone, and 2D6 and 2C18 for oxycodone).

Researchers also established the following positive controls for the system: troleandomycin (TAO) with CYP3A4 metabolism of buprenorphine, oxycodone and methadone, and gemfibrozil glucuronide for CYP2C8 metabolism of buprenorphine.

Progress was made in another area in screening the inhibitory potential of three drug classes in HLM using the project's ± 15-minute pre-incubation of inhibitor with HLM and source of NADPH protocol that indicates both in vitro inhibition and TDI. This has been done for four H2-receptor antagonists, and five proton pump inhibitors (PPIs) with methadone and oxycodone at 2.0 ìM substrate concentration, and for twelve antifungal azole compounds at 20 ìM substrate for all three opioids.

In addition, for the relevant compounds (most), researchers have determined IC50 values for the inhibition of relevant CYP450s, and have performed in vivo extrapolations to estimate in vivo inhibitory potential. Further, for the relevant compounds (most), the project determined IC50 values for the inhibition of relevant CYP450s, and have performed in vivo extrapolations to estimate in vivo inhibitory potential.

Following further mechanistic studies, the project will submit manuscripts on TDI by cimetidine and PPIs. Although much remains to be done in the project's studies on in vitro inhibition of opioid metabolism, significant in-roads have been achieved.