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首页> 外文期刊>Clinical pharmacokinetics >Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression.
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Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression.

机译：瑞波西汀的临床药代动力学，瑞波西汀是一种选择性去甲肾上腺素再摄取抑制剂，用于治疗抑郁症患者。

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Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the (S,S)-(+)- and (R,R)-(-)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding. The pharmacokinetics of reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins. The primary route of reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. A number of metabolites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. In vitro studies show that reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, reboxetine should be used with caution, and a dosage reduction is indicated. Ketoconazole decreases the clearance of reboxetine, so that the dosage of reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.
机译：瑞波西汀是一种新型的选择性去甲肾上腺素抑制剂，已在抑郁症患者的治疗中进行了评估。瑞波西汀是外消旋混合物，（S，S）-（+）-对映异构体似乎是更有效的抑制剂。然而，体内（S，S）-（+）-和（R，R）-（-）-对映异构体的浓度-时间曲线下的面积比约为0.5。没有手性倒置的证据。两种对映体清除率的差异可以通过蛋白质结合的差异来解释。瑞波西汀的单次和多次口服剂量直至每天12 mg时，其药代动力学都是线性的。 1室模型可以最好地描述口服后的血浆浓度-时间曲线，平均半衰期（约12小时）与每天两次给药的建议一致。口服后瑞波西汀可被很好地吸收。绝对生物利用度为94.5％，最大浓度通常在2-4小时内达到。食物影响吸收的速率，但不影响吸收的程度。由于瑞波西汀与血浆蛋白的广泛结合（> 97％），因此瑞波西汀的分布似乎限于全身水的一小部分。瑞波西汀消除的主要途径似乎是通过肝代谢。少于10％的剂量通过肾脏清除。已经确定了通过肝氧化形成的许多代谢产物，但是瑞波西汀是血浆中主要的循环物种。体外研究表明，瑞波西汀主要被细胞色素P450（CYP）3A4代谢;不涉及CYP2D6。老年人和肝或肾功能不全患者的瑞波西汀血浆浓度升高，可能是由于代谢清除率降低。在这些人群中，应谨慎使用瑞波西汀，并应减少剂量。酮康唑降低了reboxetine的清除率，因此当同时使用CYP3A4的有效抑制剂时可能需要减少reboxetine的剂量。奎尼丁不影响瑞波西汀的体内清除率，从而确认缺乏CYP2D6的参与。瑞波西汀与劳拉西m或氟西汀之间没有药代动力学相互作用。治疗浓度的瑞波西汀对CYP1A2、2C9、2D6、2E1或3A4的体外活性没有影响。在健康志愿者中，对雷莫西芬和阿普唑仑的代谢没有影响，证实了瑞波西汀对CYP2D6和CYP3A4的影响不足。因此，瑞波西汀不太可能影响通过CYP同工酶代谢的其他药物的清除。

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