Effect of Inhibition of Cytochrome P450 Enzymes 2D6 and 3A4 on the Pharmacokinetics of Intravenous Oxycodone A Randomized, Three-Phase, Crossover, Placebo-Controlled Study
Effect of Inhibition of Cytochrome P450 Enzymes 2D6 and 3A4 on the Pharmacokinetics of Intravenous Oxycodone A Randomized, Three-Phase, Crossover, Placebo-Controlled Study
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DOI：
10.2165/11539950-000000000-00000
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
Olkkola, Klaus T.
中科院分区：
文献类型：
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作者：
Gronlund, Juha;Saari, Teijo I.;Olkkola, Klaus T.
背景和目的：羟考酮是一种p-阿片受体激动剂，主要由肝细胞色素P450(CYP)酶代谢。由于Gyp酶可以被其他药物抑制，羟考酮的药代动力学容易受到药物相互作用的影响。本研究的目的是确定帕罗西汀单独抑制CYP2D6，或帕罗西汀和伊曲康唑联合抑制CYP2D6和CYP3A4是否会改变静脉注射羟考酮的药代动力学和药理学反应。方法：我们采用随机、三阶段、交叉、安慰剂对照研究设计，在12名健康受试者中进行。受试者在接受安慰剂、帕罗西汀或帕罗西汀和伊曲康唑联合治疗4d后，静脉注射羟考酮0.1 mg/kg。测定48小时内羟考酮及其氧化代谢产物的血药浓度，并对药代动力学和药效学参数进行评价。结果：帕罗西汀对羟考酮的血药浓度影响不大。帕罗西汀和伊曲康唑联合应用后，羟考酮的平均消除半衰期从3.8h延长至6.6h(p<；0.001)，羟考酮暴露剂量增加2倍(p<；0.001)。然而，这些变化并未反映在药理反应中。结论：本研究结果表明，静脉注射羟考酮和CYP2D6抑制剂之间没有临床相关的药物相互作用。如果通过CYP3A4和2D6的两条氧化代谢途径都被抑制，静脉注射羟考酮的暴露就会大幅增加。
Background and Objective: Oxycodone is a p-opioid receptor agonist that is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes. Because GYP enzymes can be inhibited by other drugs, the pharmacokinetics of oxycodone are prone to drug interactions. The aim of this study was to determine whether inhibition of CYP2D6 alone by paroxetine or inhibition of both CYP2D6 and CYP3A4 by a combination of paroxetine and itraconazole alters the pharmacokinetics of and pharmacological response to intravenous oxycodone.Methods: We used a randomized, three-phase, crossover, placebo-controlled study design in 12 healthy subjects. The subjects were given 0.1 mg/kg of intravenous oxycodone after pre-treatments with placebo, paroxetine or a combination of paroxetine and itraconazole for 4 days. Plasma concentrations of oxycodone and its oxidative metabolites were measured over 48 hours, and pharmacokinetic and pharmacodynamic parameters subsequently evaluated.Results: The effect of paroxetine on the plasma concentrations of oxycodone was negligible. The combination of paroxetine and itraconazole prolonged the mean elimination half-life of oxycodone from 3.8 to 6.6 hours (p < 0.001), and increased the exposure to oxycodone 2-fold (p < 0.001). However, these changes were not reflected in pharmacological response.Conclusion: The results of this study indicate that there are no clinically relevant drug interactions with intravenous oxycodone and inhibitors of CYP2D6. If both oxidative metabolic pathways via CYP3A4 and 2D6 are inhibited the exposure to intravenous oxycodone increases substantially.