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 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.
Footnotes
-
Send reprint requests to: Susanne Ammon, M.D., Institute for Pharmacology and Toxicology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. E-mail:susanne.ammon{at}medizin.uni-magdeburg.de
-
The study was fully supported by the Robert Bosch Foundation, Stuttgart, Germany.
- Abbreviations used are::
- NSAIDs
- nonsteroidal anti-inflammatory drugs
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- uridine 5′-diphosphoglucuronic acid
- CV
- coefficient of variation
- Cli
- intrinsic clearance
- Received April 25, 2000.
- Accepted July 19, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|