In Vivo Interaction of Morphine and Diclofenac  

作　　者：Yoshiaki Kimura Koki Muryoi Mika Shibata Noriyuki Ozaki Kunizo Arai Yoshiaki Kimura;Koki Muryoi;Mika Shibata;Noriyuki Ozaki;Kunizo Arai(Faculty of Pharmacy, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan;Suisen Pharmacy, Fukui Pharmaceutical Association, Fukui, Japan;Department of Functional Anatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan)

机构地区：[1]Faculty of Pharmacy, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan [2]Suisen Pharmacy, Fukui Pharmaceutical Association, Fukui, Japan [3]Department of Functional Anatomy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

出　　处：《Pharmacology & Pharmacy》2016年第12期493-503,共11页药理与制药（英文）

摘　　要：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 .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 .

关 键 词：MORPHINE DICLOFENAC UDP-GLUCURONOSYLTRANSFERASE Von Frey Test 

分 类 号：R96[医药卫生—药理学]