Pharmacokinetics of ethopropazine in the rat after oral and intravenous administration.

The pharmacokinetics of the anticholinergic drug ethopropazine (ET) have been studied in the rat after intravenous (i.v.) and oral administration. After i.v. doses of 5 and 10 mg/kg ET HCl, mean +/- S.D. plasma AUC were 9836 +/- 2129 (n = 4 rats) and 13096 +/- 4186 ng h/mL (n = 5 rats), respectively. The t1/2 after 5 and 10 mg/kg i.v. doses were 17.9 +/- 3.3 and 20.9 +/- 6.0 h, respectively. The Cl and V(dss) after 5 mg/kg i.v. doses were 0.48 +/- 0.10 L/h/kg and 7.1 +/- 2.3 L/kg, respectively. Statistically significant differences were present between the 5 and 10 mg/kg dose levels in Cl and V(dss). Oral administration of 50 mg/kg ET HCl (n = 5 rats) yielded mean AUC of 2685 +/- 336 ng h/mL. Mean plasma C(max), t(max) and t1/2 after oral doses were 236 +/- 99 ng/mL, 2.2 +/- 1.4 h and 26.1 +/- 5.4 h, respectively. Less than 1% of the dose was recovered unchanged in urine and bile. Ethopropazine is extensively distributed in the rat, and has relatively slow Cl in relation to hepatic blood flow in the rat. The drug appears to be extensively metabolized in the rat, and nonlinearity is present between the 5 and the 10 mg/kg i.v. doses. The drug displayed poor bioavailability (< 5%) after oral administration.

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 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. RESULTS: 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. CONCLUSION: 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.

High-performance liquid chromatographic assay of (+/-)-ethopropazine and its enantiomers in rat plasma.

Two high-performance liquid chromatographic (HPLC) methods are described for determination of (+/-)-ethopropazine (ET) in rat plasma. After deproteination and liquid-liquid extraction, assay of (+/-)-ET was performed using either a C18 column (non-stereospecific assay) or an (alpha-R-naphthyl)ethylurea column (stereospecific assay). The UV detection was at 250 nm. Mean recovery was >85%. Both assays demonstrated excellent linear relationships between peak height ratios and plasma concentrations; quantitation limits were < or =25 ng/ml, based on 100 microl rat plasma. Accuracy and precision were <17% with both methods. Both methods were applied successfully to the measurement of ET plasma concentrations in rats given the drug intravenously.