From systemic circulation to male gametes: Comparative pharmacokinetics of ivermectin in plasma, seminal plasma, and spermatozoa of Awassi rams.

Ivermectin is commonly administered as a prophylactic or therapeutic antiparasitic treatment without specific restrictions on the reproductive period, raising concerns about potential drug exposure in reproductive tissues and semen. This study investigated the pharmacokinetic distribution of ivermectin in plasma, seminal plasma, and spermatozoa after a single subcutaneous administration of 0.2 mg/kg to Awassi rams. Blood and semen samples were collected over a 30-day period. Ivermectin concentrations were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated using noncompartmental analysis. Based on the longest individual detection time observed among the animals, ivermectin was detectable in plasma and spermatozoa for up to 25 days and in seminal plasma for up to 20 days. The peak plasma, seminal plasma, or sperm concentration (Cmax), area under the curve to the last concentration, area under the curve extrapolated to infinity, apparent volume of distribution, apparent clearance, area under the first moment curve to the last concentration, and area under the first moment curve extrapolated to infinity values differed significantly among the plasma, seminal plasma, and spermatozoa compartments (P < .05). Plasma Cmax (25.03 ± 6.44 ng/mL) was significantly higher than in seminal plasma (0.98 ± 0.42 ng/mL) and spermatozoa (5.33 ± 3.54 ng/g). The seminal plasma/plasma Cmax and AUC ratios were approximately 3.9% and 3.5%, respectively; this result may be due to tissue-specific barriers and efflux transport mechanisms (such as P-glycoprotein) that restrict drug transfer to the reproductive organs, although ram-specific transporter expression or activity data are not available and were not directly evaluated in this study. Ivermectin concentrations in spermatozoa (ng/g) were numerically approximately 5.4-fold higher than in seminal plasma (ng/mL); although these values are expressed in different units and are not directly equivalent, this difference may reflect the affinity of this lipophilic drug for the high-lipid structures of sperm cells. The plasma pharmacokinetic parameters were consistent with previously reported values in sheep. To our knowledge, this is the first study to simultaneously characterize the pharmacokinetic profiles of ivermectin in plasma, seminal plasma, and spermatozoa in rams. These findings provide reference data for ivermectin residue and reproductive safety assessments in breeding rams and highlight the need for further investigation into its effects on spermatological parameters and fertility. SIGNIFICANT STATEMENT: Ivermectin is widely used as an antiparasitic in livestock, including in breeding rams before or during the breeding season for prophylactic or therapeutic purposes, with no specific restrictions on its use during this period. This study is the first to simultaneously examine the pharmacokinetic profiles of ivermectin in plasma, seminal plasma, and spermatozoa in rams. The significantly lower ivermectin levels in seminal plasma than in plasma suggest restricted drug transfer into reproductive tissues, likely due to tissue-specific barriers and efflux transport mechanisms, including P-glycoprotein, although these mechanisms were not directly evaluated in this study. The prolonged presence of ivermectin in seminal plasma and spermatozoa suggests that the drug remains in reproductive compartments for a significant time after a single therapeutic dose.