Pharmacokinetics of letrozole and effects of its increasing doses on gonadotropins in ewes during the breeding season

• Published in: Journal of veterinary pharmacology and therapeutics 2024-05, Vol.47 (3), p.193-201
• Main Authors: Kivrak, Mehmet Bugra, Corum, Orhan, Yuksel, Murat, Turk, Erdinc, Durna Corum, Duygu, Tekeli, Ibrahim Ozan, Uney, Kamil
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; aromatase; Aromatase Inhibitors - administration & dosage; Aromatase Inhibitors - blood; Aromatase Inhibitors - pharmacokinetics; Dose-Response Relationship, Drug; enzyme-linked immunosorbent assay; ewe; Female; Follicle Stimulating Hormone - blood; follicle-stimulating hormone; FSH; Half-Life; increasing dose; intravenous injection; letrozole; Letrozole - administration & dosage; Letrozole - pharmacokinetics; luteinizing hormone; Luteinizing Hormone - blood; Merino; pharmacokinetics; proestrus; secretion; Sheep - metabolism
• ISSN: 0140-7783; 1365-2885
• DOI: 10.1111/jvp.13414

Letrozole is a non‐steroidal, third‐generation aromatase inhibitor used in humans. Although letrozole is not approved for use in animals, it is used off‐label in cases of synchronization and infertility. The aim of this study was to determine the pharmacokinetics of letrozole after a single intravenous administration at three different doses in ewes during the breeding season and its effect on gonadotropins (luteinizing hormone (LH) and follicle‐stimulating hormone (FSH)) at the beginning of proestrus. The study was carried out on 24 healthy Merino ewes. Ewes were randomly divided into four groups (n = 6) as control, 0.5, 1, and 2 mg/kg. Plasma concentrations of letrozole were measured using HPLC‐UV and were analyzed by non‐compartmental analysis. LH and FSH concentrations were measured with a commercial ELISA kit. The terminal elimination half–life (t1/2ʎz) was significantly prolonged from 11.82 to 18.44 h in parallel with the dose increase. The dose‐normalized area under the concentration–time curve (AUC) increased, and total body clearance (ClT) decreased at the 1 and 2 mg/kg doses (0.05 L/h/kg) compared with the 0.5 mg/kg dose (0.08 L/h/kg). There were no differences in the volume of distribution at steady‐state and initial (C0.083h) plasma concentration values between dose groups. The decreased ClT, prolonged t1/2ʎz, and increased AUC at increasing doses showed the nonlinear kinetic behavior of letrozole. Letrozole significantly reduced LH concentration without affecting FSH concentration at all doses. As a result, letrozole has the potential to be used in synchronization methods and manipulation of the follicular waves due to its effect on LH secretion.