Disposition of the Diastereoisomers Quinine and Quinidine in the Ovine Fetus

Abstract

The disposition of the diastereoisomers quinine and quinidine was investigated in the near-term pregnant ewe. Five sheep were administered quinine and quinidine separately in random order by a combination of bolus and 30-h iv infusion. On a subsequent occasion, four of the five sheep were also administered the two drugs simultaneously. After separate dosage, systemic clearance of quinine tended to be greater than that of quinidine (714 ± 299 versus 422 ± 146 mL/min, p = 0.08). Maternal renal clearance exhibited no stereoselectivity and represented <2% of total clearance. Simultaneous administration did not alter the disposition of either drug in the mother. After separate dosage, fetal total concentrations (C,) of quinine and quinidine were substantially lower than maternal total concentrations, as reflected in C,:Cm ratios of 0.15 ± 0.06 versus 0.10 ± 0.08, respectively. Similarly, fetal unbound concentrations (Ctu) were substantially lower than maternal unbound concentrations (Cmu; CJCmu = 0.46 ± 0.09 for quinine and 0.23 ± 0.09 for quinidine). This indicates the presence of fetal elimination of both isomers. Fetal renal clearances of quinine and quinidine were similar (0.34 ± 0.24 mL/min versus 0.38 ± 0.24 mL/min) and less than that of endogenous creatinine, indicating the absence of net renal tubular secretion. After simultaneous dosage of quinine and quinidine, C,:Cm (0.48 ± 0.24 and 0.31 ±0.19, respectively) and C,u:Cmu (0.73 ± 0.14 and 0.52 ± 0.20, respectively) were greater than for separate dosages. Fetal renal clearance of both drugs was unchanged, suggesting that the higher C(u:Cmu ratios after simultaneous dosage were due to mutual inhibition of the fetal metabolism of these drugs.