In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.

译文

近年来,在一些国家,阿片类羟考酮的使用显着增加,并取代吗啡成为阿片类药物的一线选择。有口服立即,口服缓释和静脉内使用的制剂。生物利用度高于吗啡,且变化较小。羟考酮主要由细胞色素P450 (CYP) 酶在肝脏中代谢,其中CYP3A是主要代谢途径,CYP2D6是去甲氧可酮,羟吗啡酮和去甲氧吗啡酮的次要代谢途径。羟考酮通过 µ-阿片受体发挥镇痛作用。由于等位基因功能,CYP2D6底物的代谢在个体之间有很大程度的变化。不良代谢因子 (PM) 具有两个非功能性等位基因,广泛代谢因子 (EM) 具有两个功能性等位基因的纯合或具有一个功能性等位基因的杂合,而超类代谢因子 (UM) 具有两个以上的功能性等位基因。等位基因分布存在明显的种族间差异。根据迄今为止进行的研究,与EM相比,羟考酮的浓度在PM中相似,在UM中降低。对UM的药代动力学研究不足。同时抑制CYP3A和CYP2D6会导致羟考酮浓度增加,应避免这种组合。在CYP2D6 PM中使用CYP3A抑制剂可以预期类似的效果。应避免同时使用酶诱导剂,例如利福平,圣约翰草和卡马西平,因为存在亚治疗浓度的羟考酮的风险。当吗啡的剂量可能导致不可预测的生物利用度时,例如在严重肝硬化患者中,羟考酮可能是有益的,因为与吗啡相比,羟考酮在患者之间的生物利用度具有更高且更小的变异性。

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