Pharmacokinetic Properties of Ethopropazine in Rats

(±)-Ethopropazine (ET) is an anticholinergic drug which has been used from 1950 to present in Canada for the treatment of various symptoms of Parkinson's disease (PD). ET is a phenothiazine derivative, which has an aliphatic side chain with a chiral center. It is noticeable that there is little information published about the pharmacokinetics (PK) of anticholinergic antiparkinsonism agents. In particular, no such information could be found about ET. Therefore, studies in this thesis involved development of analytical methods for the quantitation of ET in biological specimens and their use in studying the PK of ET in the rat. Two high-performance liquid chromatographic (HPLC) methods are described for the determination of (±)-ET in rat plasma. After deproteination of plasma and liquid-liquid extraction, an assay of (±)-ET was performed using either a C18 column (non-stereospecific assay) or an (a-R-naphthyl)ethylurea column (stereospecific assay). The UV detector was at 250 nm. The mean recovery was >85%. Both assays demonstrated excellent linear relationships between peak height ratios and plasma concentrations, and quantitation limits were ≤ 25 ng/mL, based on 100 µL rat plasma. Bias and precision were <17% with both methods. Both methods were applied successfully to the measurement of ET plasma concentrations in rats given the drug by various routes of administration. To determine the PK of (±)-ET, male Sprague-Dawley rats (250-350 g) were cannulated at the right jugular vein. The drug was administered by oral (50 mg/kg) gavage or iv (5 and 10 mg/kg) as a solution of (±)-ET dissolved in water:propylene glycol:ethanol (60:30:10%). After dosing, serial blood samples and total urine output were collected for 72 h. Samples were stored at —20°C and subsequently assayed for (±)-ET using the reverse phase non-stereospecific HPLC method. Under anesthesia with halothane two rats were cannulated at the bile duct and jugular vein. For these latter rats bile were collected for 3 h after iv doses of 10 mg/kg of (±)-ET HCI. Noncompartmental PK analysis was used. The PK data showed that in relation to hepatic blood flow,' (±)-ET was eliminated slowly, and the drug had a high Vdss. Compared to the 5 mg/kg iv dose, oral bioavailability of (±)-ET was <2.7%. Less than 1% of the dose was excreted unchanged in urine and bile. With an increase in dose from 5 mg/kg to 10 mg/kg iv, the AUC did not increase proportionally, and CL and Vd were increased. Therefore, based on this information ET has poor oral bioavailability in the rat, and appears to possess nonlinear PK between 5 and 10 mg/kg. The lack of recovery of unchanged drug in the urine and bile suggests extensive metabolism. The plasma protein binding of drug was studied in vitro by equilibrium dialysis in quadruplicate at 150, 500, 2000 and 4000 ng/mL for eachenantiomer. Samples were dialyzed at 37°C for 3 h. Samples were assayed using the stereoselective HPLC -method. The fu (unbound fraction) was significantly increased (p<0.05) at concentrations >500 ng/mL. Both ET enantiomers were found to be highly bound to plasma protein and saturation occurred at concentrations >500 ng/mL. Finally, to evaluate stereoselective tissue distribution of ET enantiomers in rats, male Sprague-Dawley rats (250-350 g) were cannulated at the right jugular vein. After iv administration of (±)-ET HCI (10 mg/kg), 15 rats were sacrificed at different time points (0.5, 3, 6, 12 and 24 h; n = 3/point) post dose. Blood, brain and heart tissues were collected and frozen at -20°C until assayed. Three parts of the brain, namely substantia nigra, striatum and cortex were excised for study. Tissues (-20 mg/sample) were homogenized prior to extraction with phosphate buffer (pH=5.9). The results showed that the ET enantiomers entered into the tissues rapidly with the maximum concentration occurring at 0.5 h (the first sample collection). No stereoselectivity was observed for ET. ET was distributed differentially in the following order brain > heart > plasma, however, similar tissue concentrations were found in the three brain regions examined.

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