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

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.

For in vivo assessment of ET enantiomer concentrations, rats with implanted jugular vein cannulae were injected with 10 mg/kg of (+/-)-ET HCl. At selected times after dosing, rats were sacrificed and heart, brain, and plasma were collected. Equilibrium dialysis was used to determine the unbound fraction of ET in rat plasma over a concentration range of 150 to 4000 ng/mL of each enantiomer. A stereospecific assay was used to measure concentrations of ET enantiomer.

No stereoselectivity was observed in plasma or tissues after iv dosing. Area under the concentration vs. time curves indicated that highest uptake of ET occurred in brain tissue, followed by heart tissues, then plasma. There was no noticeable difference between concentrations of ET enantiomers in different parts of brain (substantia nigra, cortex, or striatum). There was no observed stereoselectivity 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 concentrations below and above that range.

Ethopropazine displays nonstereoselectivity in its pharmacokinetics. The drug shares distribution features similar to those of other phenothiazine derivatives. Based on the in vitro plasma protein binding results, there appears to be saturation of some, but not all, plasma binding proteins of ET within the range of concentrations studied.