Abstract
The number of studies on possible pharmacokinetic interactions between opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used in combination for the treatment of chronic pain, is limited. In rats, the major metabolic pathway of morphine is glucuronidation to morphine-3-glucuronide (M3G) by UDP-glucuronosyltransferase. In this study, we investigated the influence of diclofenac (NSAID) on the formation of M3G in vitro using rat liver tissue homogenates. Competitive inhibition of M3G formation by diclofenac was observed with an average Ki of 19.9 μM. Because these in vitro findings suggested that a pharmacokinetic interaction occurs in vitro , we investigated whether diclofenac inhibits the glucuronidation of morphine in rats. A single dose of diclofenac increased serum concentrations of both morphine and M3G and showed a higher analgesic efficacy in the Von Frey test. Furthermore, diclofenac caused a net decrease in morphine urine concentrations, but the excretion of M3G through biliary and urinary routes was unchanged. These results demonstrated that in contrast to in vitro data a single dose of diclofenac did not alter the glucuronidation of morphine in vitro .
Highlights
Various studies have demonstrated a synergistic analgesic effect of opioid-nonsteroidal anti-inflammatory drugs (NSAIDs) combinations [1] [2] [3]
We investigated the influence of diclofenac (NSAID) on the formation of M3G in vitro using rat liver tissue homogenates
Competitive inhibition of M3G formation by diclofenac was observed with an average Ki of 19.9 μM. Because these in vitro findings suggested that a pharmacokinetic interaction occurs in vivo, we investigated whether diclofenac inhibits the glucuronidation of morphine in rats
Summary
Various studies have demonstrated a synergistic analgesic effect of opioid-NSAID combinations [1] [2] [3]. This synergistic effect is considered to be because of known different pharmacodynamic mechanisms of the two groups—opioids act via opioid receptors in the central nervous system and NSAIDs affect the synthesis of prostaglandins by inhibiting cyclooxygenase. Because morphine clearance is dependent on UGTs, its inhibition by diclofenac may lead to decreased M3G formation, modifying the total effect of opioid. Because in vitro findings may not necessarily be of clinical relevance, we aimed to investigate in vivo whether diclofenac inhibits morphine glucuronidation in rats with regard to pharmacokinetics and analgesic efficacy
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