Ammon S, von Richter O, Hofmann U, Thon K P, Eichelbaum M, Mikus G
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Drug Metab Dispos. 2000 Oct;28(10):1149-52.
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.
对于阿片类镇痛药与非甾体抗炎药（NSAIDs）之间可能存在的药代动力学相互作用，人们了解甚少，而这两类药物常用于联合治疗慢性疼痛。弱阿片类药物可待因的主要代谢途径是葡萄糖醛酸化生成可待因-6-葡萄糖醛酸。因此，我们使用人肝组织匀浆在体外研究了非甾体抗炎药双氯芬酸对可待因-6-葡萄糖醛酸形成的影响。可待因-6-葡萄糖醛酸的形成呈现单酶米氏动力学，平均最大反应速度（V(max)）为93.6±35.3 pmol/mg/min。观察到双氯芬酸对可待因-6-葡萄糖醛酸化有非竞争性抑制作用，平均抑制常数（K(i)）为7.9 microM。这些体外研究结果表明体内发生了药代动力学相互作用，这有待通过人体相互作用研究来证实。可以推测，在葡萄糖醛酸化受到抑制的情况下，可用于其他途径（尤其是O-去甲基化生成吗啡）的可待因量会增加，从而导致更高的吗啡血清水平，进而产生更高的镇痛效果。
