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Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.
Pearson, David; Weiss, H Markus; Jin, Yi; Jaap van Lier, Jan; Erpenbeck, Veit J; Glaenzel, Ulrike; End, Peter; Woessner, Ralph; Eggimann, Fabian; Camenisch, Gian.
Afiliação
  • Pearson D; 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.) david.pearson@novartis.com.
  • Weiss HM; 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.).
  • Jin Y; 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.).
  • Jaap van Lier J; 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.).
  • Erpenbeck VJ; 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.).
  • Glaenzel U; 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.).
  • End P; 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.).
  • Woessner R; 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.).
  • Eggimann F; 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.).
  • Camenisch G; 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 ; 45(7): 817-825, 2017 07.
Article em En | MEDLINE | ID: mdl-28442499
ABSTRACT
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; 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 [14C]-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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Microssomos Hepáticos / Receptores de Prostaglandina / Receptores Imunológicos / Hepatócitos / Ácidos Indolacéticos Limite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridinas / Microssomos Hepáticos / Receptores de Prostaglandina / Receptores Imunológicos / Hepatócitos / Ácidos Indolacéticos Limite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article