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Inhibition of In Vitro Metabolism of Opioids by Skeletal Muscle Relaxants
Author(s) -
Moody David E.,
Fu Yueqiao,
Fang Wenfang B.
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12999
Subject(s) - chlorzoxazone , pharmacology , meprobamate , chemistry , muscle relaxant , tizanidine , cyp3a4 , skeletal muscle , metabolite , oxycodone , microsome , opioid , metabolism , cytochrome p450 , in vitro , medicine , anesthesia , biochemistry , cyp2e1 , receptor , spasticity
The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications opioids buprenorphine, methadone and oxycodone. The compounds [solubility‐limited concentration (μM) studied] were as follows: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes ± pre‐incubation, screened with pathway‐specific c DNA ‐expressed cytochrome P450s (r CYP ), and then IC 50 values determined using either 8‐concentration tests for those where the r CYP screen suggested an IC 50 was achievable, or a 3‐concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable. These results were then extrapolated to determine an inhibitory potential. Six pathway inhibitor combinations were identified with a moderate inhibitory potential (≥2.0 < 5.0): five with chlorzoxazone, R‐ EDDP , S‐ EDDP and noroxycodone production by CYP 3A4, and R‐ and S‐ EDDP production by CYP 2B6; and one for the meprobamate effect on noroxycodone production by CYP 3A4. An additional eleven combinations were found with a weak inhibitory potential (≥1.25 < 2.0): five with carisoprodol, two each with methocarbamol and meprobamate, and one each with metaxalone and orphenadrine. This represents the first comprehensive study of the inhibitory effect of this class of drugs and suggests that some of them may produce significant drug–drug interactions with opioids that are frequent comedications with skeletal muscle relaxants.