Van Haarst A D, Van Gerven J M, Cohen A F, De Smet M, Sterrett A, Birk K L, Fisher A L, De Puy M E, Goldberg M R, Musson D G
Centre for Human Drug Research, Leiden, The Netherlands.
Br J Clin Pharmacol. 1999 Aug;48(2):190-6. doi: 10.1046/j.1365-2125.1999.00011.x.
The new 5-HT1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide.
In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly.
Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11-1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were prolonged.
Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.
新型5-羟色胺1B/1D激动剂利扎曲普坦（MK-0462）最近已获准用于偏头痛治疗。其主要代谢途径是通过单胺氧化酶-A（MAO-A）。抗抑郁药如MAO-A抑制剂吗氯贝胺可用于慢性头痛综合征患者。因此，本研究旨在调查利扎曲普坦与吗氯贝胺之间的相互作用。
在一项双盲、随机、安慰剂对照、两阶段交叉研究中，12名健康年轻志愿者（6名男性，6名女性）接受吗氯贝胺（每日两次，每次150毫克）或安慰剂治疗4天。在第4天，给予单剂量利扎曲普坦（10毫克），随后采集血样和尿样以检测利扎曲普坦和N-单去甲基利扎曲普坦。还评估了MAO-A抑制标志物3,4-二羟基苯乙二醇（DHPG）的血浆浓度。定期测量仰卧位和站立位血压。
两种治疗耐受性均良好。在给予吗氯贝胺期间，服用利扎曲普坦后仰卧位舒张压升高幅度增大。吗氯贝胺对MAO的抑制作用可从DHPG水平持续下降（平均43%）推断出来。当利扎曲普坦与吗氯贝胺合用时，与安慰剂相比，利扎曲普坦及其N-单去甲基代谢物的血浆药物浓度-时间曲线下面积分别增加2.2倍（90%可信区间，1.93-2.47）和5.3倍（90%可信区间，4.81-5.91）。利扎曲普坦及其N-单去甲基代谢物的血浆药物峰浓度分别增加1.4倍（90%可信区间，1.11-1.80）和2.6倍（90%可信区间，2.23-3.14），且两者的半衰期均延长。
吗氯贝胺通过抑制MAO-A抑制利扎曲普坦及其活性N-单去甲基代谢物的代谢。因此，吗氯贝胺可能会显著增强利扎曲普坦的作用。不建议同时服用吗氯贝胺和利扎曲普坦。
