Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain.
Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain.
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DOI：
10.1038/npp.2014.214
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发表时间：
2015-02
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司来吉兰(L-丙烯基)是一种选择性的、不可逆转的单胺氧化酶B(MAO-B)抑制剂，剂量为10 mg/d，用于治疗帕金森病。然而，对照研究表明，大剂量口服司来吉兰和透皮用司来吉兰具有抗抑郁活性，这表明当血浆中司来吉兰水平升高时，大脑MAO-A也可能受到抑制。Zydis司来吉兰(Zelapar)是司来吉兰的口腔崩解制剂，与同等剂量的常规司来吉兰相比，它通过口腔粘膜吸收，产生更高水平的司来吉兰和更少的苯丙胺代谢产物。虽然有间接证据表明高剂量的司来吉兰失去了对MAO-B的选择性，但没有直接证据表明它也抑制人类大脑中的MAO-A。我们用正电子发射断层扫描和MAO-A放射性示踪剂[11C]Clorgyline测定了18名健康男性和3名接受司来吉兰透皮贴剂(Emsam贴剂，6 mg/d)治疗28天后的脑MAO-A。我们还测量了来自10 mg组的三名受试者的多巴胺转运体的可用性。塞来吉兰10 mg剂量显著抑制MAO-A(36.9±19.7%，范围11-70%，p<；0.007)，而Emsam也抑制MAO-A(33.2±28.9%，范围9-68%，P=0.10)。我们的结果提供了第一个直接证据，证明了司来吉兰制剂对人类大脑MAO-A的抑制作用，目前认为司来吉兰除了针对MAO-B，还针对大脑MAO-A，但尚未得到证实。
Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [11C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9–68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.
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