Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (D.P., H.M.W., Y.J., V.J.E., U.G., P.E., R.W., F.E., G.C.); PRA International, Early Development Services, Zuidlaren, the Netherlands (J.J.v.L.)
Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (D.P., H.M.W., Y.J., V.J.E., U.G., P.E., R.W., F.E., G.C.); PRA International, Early Development Services, Zuidlaren, the Netherlands (J.J.v.L.).
Drug Metab Dispos. 2017 Jul;45(7):817-825. doi: 10.1124/dmd.117.075358. Epub 2017 Apr 25.
Fevipiprant is a novel oral prostaglandin D receptor 2 (DP; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.
非索罗定是一种新型的口服前列腺素 D 受体 2（DP；也称为 CRTh2）拮抗剂，目前正在开发用于治疗严重哮喘和特应性皮炎。我们在健康受试者中单次口服 200mg[C]标记的非索罗定后，研究了非索罗定的吸收、分布、代谢和排泄特性。通过液相色谱-串联质谱和放射性测量分析非索罗定及其代谢物，并进行体外机制研究以调查清除途径和共价血浆蛋白结合。非索罗定的生物转化主要涉及一种无活性的酰基葡萄糖醛酸（AG）代谢物，该代谢物在血浆和排泄物中被检测到，占排泄的药物相关物质的 28%。AG 代谢物被发现与人体血浆蛋白（可能是白蛋白）发生共价结合，但体外与肝蛋白的共价结合可以忽略不计。排泄主要以原型非索罗定的形式通过尿液和粪便，表明通过肾脏和可能的胆汁排泄进行清除。非索罗定被发现是转运体有机阴离子转运蛋白 3（OAT3；肾脏摄取）、多药耐药基因 1（MDR1；可能的胆汁排泄）和有机阴离子转运多肽 1B3（OATP1B3；肝脏摄取）的底物。非索罗定的消除通过几种尿苷 5'-二磷酸葡萄糖醛酸转移酶（UGT）酶的葡萄糖醛酸化以及直接排泄发生。这些平行的消除途径导致该化合物发生主要药物相互作用或药物遗传学/种族变异性的风险较低。
