Absorption, distribution, metabolism, and excretion of linzagolix after a single oral dose in rats and monkeys.

Abstract

1. Linzagolix is an orally available gonadotropin-releasing hormone antagonist used to treat female-specific diseases, such as uterine fibroids and endometriosis.2. After a single dose of [14C]linzagolix or linzagolix to female rats and monkeys, linzagolix exhibited the absorption-distribution-metabolism-excretion characteristics of acidic drugs owing to the presence of a carboxylic acid moiety in its structure.3. Linzagolix showed low total clearance, high oral bioavailability, and high plasma exposure associated with high solubility, low metabolic clearance, and entero-hepatic circulation. Linzagolix had a low-volume distribution with limited tissue distribution associated with high plasma protein binding. These absorption-distribution-metabolism-excretion characteristics were comparable between the two species.4. After a single oral dose of [14C]linzagolix to rats, radioactivity was rapidly distributed to almost all tissues; however, the extent of the tissue distribution was limited and decreased in parallel with elimination from the blood.5. In both species, linzagolix was identified as the primary circulating and excretory component. The major biotransformation pathways of linzagolix were two O-demethylations and O-debenzylation. Additionally, sulphate conjugates of O-demethylated metabolites were detected in rats.6. The major excretion route of linzagolix was faecal excretion via the bile in its unchanged form.