Effect of buprenorphine on CYP3A activity in rat and human liver microsomes

Buprenorphine is a partial opioid agonist available in France as an alterna tive to methadone in the treatment of opiate-dependent individuals. Twenty deaths have been reported in patients who have ingested buprenorphine in co mbination with benzodiazepines. Since buprenorphine and many benzodiazepine s are CYP3A substrates, the effect of buprenorphine on CYP3A activity was e xamined in order to assess the likelihood of a pharmacokinetic interaction. The formation of 6 beta-hydroxytestosterone was measured in dexamethasone- induced rat liver microsomes and in human liver microsomes under control co nditions and in the presence of buprenorphine. Buprenorphine was found to b e a weak inhibitor of CYP3A with a 50% decrease in enzyme activity occurrin g at a concentration of 118 mu M (IC50) in human liver microsomes. IC50 was 0.3 mu M for ketoconazole in the same system. Since the IC50 for buprenorp hine is roughly 2000 times higher than typical plasma concentrations, this drug is unlikely to cause clinically significant inhibition of CYP3A in pat ients. Excessive CNS depression due to the combination of buprenorphine and benzodiazepines is most likely due to additive or synergistic pharmacologi c effect unrelated to a pharmacokinetic interaction between the drugs.