title: In vitro interaction of codeine and diclofenac.
abstract: 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 average V(max) of 93.6 +/- 35.3 pmol/mg/min. A noncompetitive inhibition of codeine-6-glucuronidation by diclofenac was observed with an average K(i) of 7.9 microM. 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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. susanne.ammon@medizin.uni-magdeburg.de
authors.forename: S
authors.initials: S
authors.lastname: Ammon
authors.forename: O
authors.initials: O
authors.lastname: von Richter
authors.forename: U
authors.initials: U
authors.lastname: Hofmann
authors.forename: K P
authors.initials: KP
authors.lastname: Thon
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: G
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003061:Codeine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D004008:Diclofenac / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009294:Narcotics / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009294:Narcotics; D004008:Diclofenac; C061773:codeine-6-glucuronide; D003061:Codeine