LC-MS/MS Analyzing Praziquantel and 4-Hydroxypraziquantel Enantiomers in Black Goat Plasma and Mechanism of Stereoselective Pharmacokinetics

Abstract

Praziquantel (PZQ) is the most effective treatment for schistosomiasis, commonly administered as a racemic mixture of the two enantiomers. Despite many reports on the pharmacokinetics of PZQ, the stereoselective pharmacokinetics of PZQ and its major metabolite 4-hydroxypraziquantel (4-OH-PZQ) remain poorly understood in goats. In this study, the chiral LC-MS/MS method was further optimized for separating and quantifying PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ and their enantiomers and then applied for the molecular pharmacokinetics of three analytes in black goat plasma. The findings showed that PZQ was rapidly absorbed and metabolized to 4-OH-PZQ. The C_max of trans-4-OH-PZQ was about 3 times and 6 times higher than those of cis-4-OH-PZQ and PZQ, respectively. The stereoselectivity of the PZQ and cis-4-OH-PZQ enantiomers was insignificant in black goat plasma (p > 0.05), whereas the trans-4-OH-PZQ enantiomers exhibited obvious stereoselectivity (p < 0.05). The C_max of S-trans-4-OH-PZQ were ~3.1 times higher than that of R-trans-4-OH-PZQ. Further computer simulations indicated that these differences in the stereoselectivity might mainly stem from the different binding energies of the corresponding R- and S-enantiomers of the target analytes to black goat plasma albumin. It has guiding significance for the research on the stereoselectivity of chiral veterinary drugs and their precision medication.