RT Journal Article
SR Electronic
T1 In Vitro Interaction of Codeine and Diclofenac
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1149
OP 1152
VO 28
IS 10
A1 Susanne Ammon
A1 Oliver von Richter
A1 Ute Hofmann
A1 Klaus-Peter Thon
A1 Michel Eichelbaum
A1 Gerd Mikus
YR 2000
UL http://dmd.aspetjournals.org/content/28/10/1149.abstract
AB 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 NSAID diclofenac on the formation of codeine-6-glucuronide in vitro, using human liver tissue homogenate. The formation of codeine-6-glucuronide exhibited single enzyme Michaelis-Menten kinetics with an averageVmax of 93.6 ± 35.3 pmol/mg/min. A noncompetitive inhibition of codeine-6-glucuronidation by diclofenac was observed with an average Ki of 7.9 μM. These in vitro findings suggest that a pharmacokinetic interaction occurs in vivo, which 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 codeine available for other pathways especially O-demethylation to morphine is increased, resulting in higher morphine serum levels and therefore higher analgesic efficacy. The American Society for Pharmacology and Experimental Therapeutics