Metabolism and disposition of zamicastat in rats.

Abstract

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [¹⁴C]-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.