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

Kivrak, Mehmet BugraCorum, OrhanYuksel, MuratTurk, ErdincCorum, Duygu DurnaTekeli, Ibrahim OzanUney, Kamil2024-09-182024-09-1820240140-77831365-2885https://doi.org/10.1111/jvp.13414https://hdl.handle.net/20.500.12483/9956Letrozole 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 (t(1/2 lambda z)) 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 (Cl-T) 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 (C-0.083h) plasma concentration values between dose groups. The decreased ClT, prolonged t(1/2 lambda z), 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.eninfo:eu-repo/semantics/closedAccesseweFSHincreasing doseletrozoleLHpharmacokineticsPharmacokinetics of letrozole and effects of its increasing doses on gonadotropins in ewes during the breeding seasonArticle47319320110.1111/jvp.1341437920137WOS:001096172400001Q2