In vitro interaction of codeine and diclofenac

There is very limited knowledge about possible pharmacokinetic interactions between opioid analgesics and nonsteroidal antiinflammatory drugs (NSAIDs) , which are commonly used in combination for the treatment of chronic pain. The major metabolic pathway of the weak opioid codeine is glucuronidation to codeine-6-glucuronide. Therefore we investigated the influence of the NS AID diclofenac on the formation of codeine-6-glucuronide in vitro, using hu man liver tissue homogenate. The formation of codeine-6- glucuronide exhibi ted single enzyme Michaelis-Menten kinetics with an average V-max of 93.6 /- 35.3 pmol/mg/min. A non-competitive inhibition of codeine-6-glucuronidat ion by diclofenac was observed with an average K-i of 7.9 mu M. These in vi tro findings suggest that a pharmacokinetic interaction occurs in vivo, whi ch has to be confirmed by an interaction study in human subjects. It can be speculated that in case of inhibition of glucuronidation, the amount of co deine available for other pathways especially O-demethylation to morphine i s increased, resulting in higher morphine serum levels and therefore higher analgesic efficacy.