Disposition of ethopropazine enantiomers in the rat: Tissue distribution and plasma protein binding.

Purpose: To determine the in vitro plasma protein binding, and the in vivo brain, heart and plasma concentrations of ethopropazine (ET) enantiomers in the rat after iv doses. Methods: For in vivo assessment of ET enantiomer c oncentrations, rats with implanted jugular vein cannulae were injected with 10 mg/kg of (+/-)-ET HCl. At selected times after dosing, rats were sacrif iced and heart, brain, and plasma were collected. Equilibrium dialysis was used to determine the unbound fraction of ET in rat plasma over a concentra tion range of 150 to 4000 ng/mL of each enantiomer. A stereospecific assay was used to measure concentrations of ET enantiomer. Results: No stereosele ctivity was observed in plasma or tissues after iv dosing. Area under the c oncentration vs. time curves indicated that highest uptake of ET occurred i n brain tissue, followed by heart tissues, then plasma. There was no notice able difference between concentrations of ET enantiomers in different parts of brain (substantia nigra, cortex, or striatum). There was no observed st ereoselectivity in plasma protein binding of ET enantiomers in rat plasma. Saturation of binding to plasma proteins was observed between 500 and 2000 ng/mL of each ET enantiomer, but unbound fraction was constant at concentra tions below and above that range. Conclusion: Ethopropazine displays nonste reoselectivity in its pharmacokinetics. The drug shares distribution featur es similar to those of other phenothiazine derivatives. Based on the in vit ro plasma protein binding results, there appears to be saturation of some, but not all, plasma binding proteins of ET within the range of concentratio ns studied.