Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Drug Discovery, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Clin Pharmacol Ther. 2018 Dec;104(6):1260-1267. doi: 10.1002/cpt.1087. Epub 2018 May 10.
Serotonin (5-HT) is synthesized from dietary tryptophan (Trp) and plays an important role in numerous diseases of the central nervous system and periphery. Stable isotope tracers enable safe monitoring of metabolic rates. Here we demonstrate measurement of peripheral 5-HT synthesis in healthy subjects by monitoring the produced [ C ]-5-HT (h-5-HT) in EDTA-whole blood from three doses of orally administered [ C ]-Trp (h-Trp) tracer. h-Trp was rapidly absorbed and distributed in a multiphasic manner, followed by a slower terminal elimination phase. The h-5-HT synthesis rate was dependent on h-Trp dose, appeared linear up to 12 hours postdose, and could be reliably assessed for the two highest doses. The human data was compared to similar studies in rats and dogs, finding larger interspecies differences in the h-5-HT synthesis rate than in 5-HT levels. In future studies, the h-5-HT synthesis rate can be used to assess disease-dysregulated 5-HT synthesis or quantify the pharmacodynamics of 5-HT synthesis inhibitors.
血清素（5-HT）由膳食色氨酸（Trp）合成，在中枢神经系统和外周神经系统的许多疾病中发挥重要作用。稳定同位素示踪剂可安全监测代谢率。在这里，我们通过监测口服给予[C] - Trp（h-Trp）示踪剂后三个剂量的 EDTA-全血中产生的[C] - 5-HT（h-5-HT），证明了健康受试者外周 5-HT 合成的测量。h-Trp 被快速吸收并以多相方式分布，随后是较慢的末端消除相。h-5-HT 合成率取决于 h-Trp 剂量，在给药后 12 小时内呈线性，并且可以可靠地评估两个最高剂量。将人体数据与大鼠和狗的类似研究进行比较，发现 h-5-HT 合成率的种间差异大于 5-HT 水平的种间差异。在未来的研究中，h-5-HT 合成率可用于评估疾病失调的 5-HT 合成或量化 5-HT 合成抑制剂的药效动力学。
