Doxycycline hyclate in late-term pregnant mares: pharmacokinetics, diffusion to the fetoplacental unit and safety in the resulting foal

Abstract

Doxycycline is a second-generation tetracycline with excellent tissue penetration, high-protein-binding, and 5-10-fold higher lipophilic character than tetracycline. It is used to treat difficult-to-identify and atypical pathogens in diseases such as granulocytic anaplasmosis, Potomac fever, Lyme disease, and placentitis caused by Leptospira and nocardioform Actinomycetes. Despite routine use of doxycycline in pregnant mares, there is no data on their pharmacokinetics during pregnancy, transplacental diffusion, or potential toxicity to the fetus and resulting foal. This study aimed to determine the pharmacokinetics of doxycycline in the late-pregnant mare, its diffusion to the fetoplacental unit and its safety in the neonate. The study hypothesizes that doxycycline crosses the equine fetoplacental unit after administration during late-term pregnancy and is safe for the resulting foal. In experiment 1, six mares received a dose of compounded doxycycline hyclate (10mg/kg, p.o.) at 300d of gestation. Doxycycline plasma concentrations were measured with LC-MS/MS at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48h after administration to confirm absorption and pharmacokinetics. The compounded doxycycline used herein was absorbed rapidly, and maximum plasma concentrations were achieved in 0.79h. Pharmacokinetic parameters of the doxycycline were similar to previous studies using commercial canine preparations. In experiment 2, transplacental diffusion and safety to the resulting foal were studied after administration of repeated doses ofdoxycycline to late-term pregnant mares. Seven mares received doxycycline (10mg/kg p.o. q12h) from 320d of gestation until foaling, and six gestationally-age-matched mares served as controls. Once impending signs of imminent parturition were detected coupled with mammary gland secretion pH ≤6.4, foaling was induced with oxytocin (10-units, intramuscularly) to ensure a controlled sampling of fetal fluids. Fetal fluids and foal synovial fluids were harvested at foaling to determine doxycycline concentrations with LC-MS/MS. After parturition, foals had daily clinical examinations, blood chemistry, and complete blood cell counts performed for seven days. Shapiro-Wilk was used to test normal distribution and data were analyzed with ANOVA and Tukey's as post hoc. Mares received doxycycline on average for 15±2d (range 9-23d). No adverse side effects were associated with doxycycline treatment, and complete blood cell count or blood chemistry pre- and post-partum remained within normal reference ranges. Gestation length for doxycycline-treated mares (335±2d) was similar to controls (339±4) (P=0.4). Concentrations of doxycycline were 9-fold higher in the allantoic fluid (73.5±13.9ng/mL) than amniotic fluid (8.3±3.3ng/mL) and 1.5-fold higher in the foal's plasma (35.5±4.3ng/mL than its synovial fluid (23.6±4.3ng/mL). In conclusion, doxycycline was well-absorbed and detectable in fetal fluids, foal plasma, and synovial fluid, and no adverse effects were observed in mares nor their foals.