Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan.
Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan; Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, Japan.
Drug Metab Pharmacokinet. 2020 Dec;35(6):571-573. doi: 10.1016/j.dmpk.2020.07.001. Epub 2020 Jul 26.
Polymorphic human and cynomolgus macaque flavin-containing monooxygenases (FMO) 3 are important oxygenation enzymes for nitrogen-containing drugs. Inter-animal variability of FMO3-dependent drug oxygenations in vivo is suspected in cynomolgus macaques because such variability is evident in humans. Therefore, this follow-up study was performed to investigate the pharmacokinetics of orally administered deuterium-labeled trimethylamine in three cynomolgus macaques genotyped for FMO3. Trimethylamine-d was rapidly absorbed and attained plasma concentrations greater than the background levels of non-labeled trimethylamine. Trimethylamine-d was then converted to trimethylamine-dN-oxide. The half-lives, maximum plasma concentrations, and areas under the curve for trimethylamine-d and its N-oxygenated metabolite and the total clearance for orally administered trimethylamine-d were not different among the heterozygote for Q506K FMO3, the heterozygote for V325I FMO3, and the heterozygote for both S99N and F510S FMO3. Trimethylamine N-oxygenation activities mediated by liver microsomes prepared from the same three animals were not substantially different. However, recombinant proteins of the corresponding cynomolgus FMO3 variants showed apparent reduced trimethylamine N-oxygenation activities compared with the wild-type proteins. This study suggests only limited polymorphic effects on the in vivo catalytic function of cynomolgus FMO3. These findings yield important insights in terms of both quantitative and qualitative variations of polymorphic FMO3 in cynomolgus liver.
人源和食蟹猴黄素单加氧酶 3（FMO3）是含氮药物重要的加氧酶。由于人类中存在这种变异性，因此怀疑食蟹猴中 FMO3 依赖性药物氧化在体内存在个体间变异性。因此，进行了这项后续研究，以研究三种 FMO3 基因型的食蟹猴口服氘标记三甲胺的药代动力学。三甲胺-d 被迅速吸收，并达到大于非标记三甲胺背景水平的血浆浓度。然后，三甲胺-d 转化为三甲胺-dN-氧化物。在 FMO3 的 Q506K 杂合子、V325I FMO3 杂合子和 S99N 和 F510S FMO3 双杂合子中，三甲胺-d 和其 N-氧化代谢物的半衰期、最大血浆浓度和曲线下面积以及口服给予的三甲胺-d 的总清除率没有差异。从这三只动物制备的肝微粒体介导的三甲胺 N-氧化活性没有明显差异。然而，相应的食蟹猴 FMO3 变体的重组蛋白与野生型蛋白相比，表现出明显降低的三甲胺 N-氧化活性。这项研究表明，食蟹猴 FMO3 的体内催化功能仅有有限的多态性影响。这些发现为食蟹猴肝脏中多态性 FMO3 的定量和定性变化提供了重要的见解。
