Pharmacokinetics and mass balance of vericiguat in rats and dogs and distribution in rats

Abstract

1. Vericiguat is a soluble guanylate cyclase stimulator. The pharmacokinetics, absorption, metabolism, and excretion properties of vericiguat in rats and dogs and the distribution in rats are reported. [¹⁴C]-labelled vericiguat was studied in intact and bile duct-cannulated rats (oral and intravenous administration), and dogs (oral administration).

2. Vericiguat reached maximum plasma concentrations at 1–3 h after oral administration. Absolute bioavailability was moderate in rats and high in dogs. Vericiguat was the most abundant component in plasma of rats and dogs.

3. After oral administration to rats, radioactivity was widely distributed. Penetration into the brain was minimal. Elimination was rapid from most tissues in rats. Most of the radioactivity was excreted in faeces (rat: 81%, dog: 89%), while low amounts were excreted in urine (rat: 11%, dog: 4%). Clearance routes in both species were unchanged excretion and metabolism via glucuronidation and oxidative reactions. After intravenous administration to bile duct-cannulated rats, a relevant proportion of the dose (30%) underwent direct excretion into the gastrointestinal tract as unchanged vericiguat.

Keywords:

• Absorption
• distribution
• metabolism
• and excretion (ADME)
• blood–brain barrier
• pharmacokinetics
• autoradiography
• rats
• preclinical
• sGC stimulator

Acknowledgements

We would like to thank Christine Cyrus for editorials, Martina Blombach for technical support in analysing the mass balance studies, Dirk Gäfke for technical support with the in vitro incubations and metabolite identification, Beate Schnippert, Sara Walin, Andreas Wirth, Daniela Asmussen, Stephan Heffels and Christian Motzkus for carrying out the animal experiments, Erdmuthe Schaub and Andreas Leckebusch for radioactivity measurements, Nicola Busch, Jasmin Percher, and Renate Kruk for pharmacokinetic evaluations, and G Löhr and Ursula Aichinger for bioanalytical measurements.

Editorial support, including data checking, figure preparation, formatting, proofreading, and submission, was provided by Nadia Rafei and Ian Norton of Scion, London, UK, according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M15-0288) and funded by Bayer AG.

Disclosure statement

The authors of this paper are employees at BAYER AG and have not received financial support from any other institution.

Additional information

Funding

This work was supported by Bayer AG, Wuppertal, Germany.