Metabolism and disposition of zamicastat in rats.

Data de publicação: Data Ahead of Print: 10/10/2024

Autores da FMUP

Patrício Manuel Vieira Araújo Soares Da Silva

Autor

Participantes de fora da FMUP

Araújo F
Dória ML
Beliaev A
Kiss LE
Bonifácio MJ
Holenz J
Loureiro AI

Unidades de investigação

Biomedicina

Abstract

The metabolism and disposition of zamicastat, a reversible dopamine ß-hydroxylase (DßH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [(14)C]-zamicastat.Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles.Maximum plasma concentration of zamicastat-related radioactivity occurred in the first hours, remaining quantifiable up to 144 h. The unchanged zamicastat plasma peak was 2 h post-dose and declined to low levels over 24 h.Zamicastat metabolism occurs largely during the first 8 h with only one metabolite identified in the latest time-point (96 h), the isothiocyanic acid/thiocyanic acid (tautomeric forms). Zamicastat metabolic pathway involved multiple reactions comprising desulphurisation, oxidative desulphurisation, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isothiocyanic acid/thiocyanic acid.

Dados da publicação

ISSN/ISSNe:: 1366-5928, 1366-5928
Tipo:: Article
Páginas:: 1-12
DOI:: 10.1080/00498254.2024.2411993

Documentos

Não há documentos

Métricas

Filiações

Araújo F:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Dória ML:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Beliaev A:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Kiss LE:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Bonifácio MJ:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Holenz J:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal
Soares-da-Silva P:: Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of Porto, Porto, Portugal

MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal
Loureiro AI:: Department of Research and Development, BIAL - Portela & Ca. S.A., São Mamede do Coronado, Portugal

Keywords

Zamicastat; disposition; metabolism; pharmacokinetics; rat

Proyectos asociados

Modelling Propofol pharmacokinetics and pharmacodynamics during an intravenous anaesthesia guided by the bispectral index (Bis)

Investigador Principal: Patrício Manuel Vieira Araújo Soares da Silva

Estudo Clínico Académico . 2021

Inervação simpática e mecanismos adrenérgicos locais na regulação funcional da córnea