The number of studies on possible pharmacokinetic interactions between opioid\nanalgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly\nused in combination for the treatment of chronic pain, is limited. In rats, the\nmajor metabolic pathway of morphine is glucuronidation to morphine-3-glucuronide\n(M3G) by UDP-glucuronosyltransferase. In this study, we investigated the influence\nof diclofenac (NSAID) on the formation of M3G in vitro using rat liver tissue homogenates.\nCompetitive inhibition of M3G formation by diclofenac was observed with\nan average Ki of 19.9 �¼M. Because these in vitro findings suggested that a pharmacokinetic\ninteraction occurs in vivo , we investigated whether diclofenac inhibits the\nglucuronidation of morphine in rats. A single dose of diclofenac increased serum\nconcentrations of both morphine and M3G and showed a higher analgesic efficacy in\nthe Von Frey test. Furthermore, diclofenac caused a net decrease in morphine urine\nconcentrations, but the excretion of M3G through biliary and urinary routes was\nunchanged. These results demonstrated that in contrast to in vitro data a single dose\nof diclofenac did not alter the glucuronidation of morphine in vivo.
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