The stereoselective pharmacokinetics of the desmethyl-phencynonate hydrochloride in beagle dogs.

The aim of this study was to investigate the chiral inversion and the stereoselective pharmacokinetic profiles of desmethyl-phencynonate hydrochloride after administration of the single isomer and its racemate to beagle dogs. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was established for determination of the stereoisomers on chiral columns in beagle dog plasma, which met all the requirements. The chiral inversion in dogs of the desmethyl-phencynonate hydrochloride were studied after administration of the single isomer or the racemic modification. The stereoselective pharmacokinetic profiles of the desmethyl-phencynonate hydrochloride were studied by assays for simultaneous isomers after administration of the racemic modification. The results showed that the absorption of the R-configuration dosed as the single isomer was higher than it dosed as the racemic modification. The AUC(0-t), AUC(0-∞), and Cmax of the S-configuration were much higher than those of R-configuration after oral administration of the racemic desmethyl-phencynonate hydrochloride. The chiral inversion of desmethyl-phencynonate isomers could not occur in dogs after administration of the R-configuration.

Optimization of Phencynonate Hydrochloride Transdermal Patch Formulation by Box-Behnken Design-response Surface Methodology / 中国药房

OBJECTIVE:To optimize the formulation of Phencynonate hydrochloride transdermal patch. METHODS:Phencynonate hydrochloride transdermal patch was prepared by solvent evaporation method. Using 48 h accumulative transdermal volume as index,single factor test and Box-Behnken design-response surface methodology were used to optimize drug dosage,the amount of transdermal enhancers azone and pressure-sensitive adhesive,and evaluate the appearance,adhesion of the formulation prepared by the best prescription. RESULTS:The optimized formulation was as follows as 263 mg drug dosage,165 mg azone, 1.94 g pressure-sensitive adhesive and 1.6 g methanol. 48 h accumulative transdermal volume of prepared patch was(119.48 ± 2.95)μ g/cm2(n=5),related error of which to predicted value was 2.48%. The prepared patch showed smooth surface and incision,good adhesiveness. CONCLUSIONS:Phencynonate hydrochloride transdermal patch is prepared successfully,its accumulative transdermal volume is in agreement with predicted standard.

Improvement of phencynonate hydrochloride on posterior circulation vertigo in rats and positive vertigo in mice / 中国药理学与毒理学杂志

OBJECTIVE To evaluate the anti-vertigo effect of phencynonate hydrochloride. METHODS To detect the improvement of phencynonate hydrochloride on cerebral blood flow, a rat model wa s es?tablished with bilateral common carotid arteries occlusion. Phencynonate hydrochloride 0.1-4.0 mg·kg-1 was ig given, twice a day for three consecutive days and the alteration of cerebral blood flow was measured with laser Doppler flowmetry. Rotating acceleration equipment was used to provocate mouse vertigo for 30 min, and the spontaneous locomotor activities were tested for occurrence of vertigo in mice. Phencynonate hydrochloride 1.4-5.6 mg·kg-1 was ig given before rotating acceleration. Gastric phenol red emptying rate was used to determine the anti-nausea effect of the test drug in mice 30 min after phencynonate hydrochloride 1.4-8.4 mg·kg-1 was ig given. RESULTS The cerebral blood flow of the rat model with bilateral common carotid arteries occlusion was reduced significantly after 24 h (P<0.01). Compared with the model group, phencynonate hydrochloride (0.5, 2.0 and 4.0 mg · kg-1) increased the cerebral blood flow in a dose-dependent manner in rats with cerebral ischemia (P<0.01). The spontaneous locomotor activities were significantly reduced after vertigo stimulation in mice (P<0.05). Compared with the model group, phencynonate hydrochloride (2.8 and 5.6 mg · kg-1) increased the movement distance and speed of vertigo mice (P<0.05). Phencynonate hydrochloride (2.8, 5.6 and 8.4 mg·kg-1) inhibited the gastric emptying of mice (P<0.05). CONCLUSION Phecynonate hydrochloride can improve the cerebral blood flow and locomotor activities in vertigo rats, while inhibiting gastric emptying, which points to the therapeutic potential of phencynonate hydrochloride for vertigo in clinic.

Establishment of Determination Method for Drug Release of Phencynonate Hydrochloride Extended Release Tablets / 中国药师

Objective:To establish the drug release determination conditions and method for phencynonate hydrochloride extended release tablets. Methods:The drug release of the tablets was determined by HPLC using a Diamonsil C18 (250 mm × 4. 6 mm, 5 μm) column with the mobile phase of acetonitrile-water-phosphoric acid-triethylamine (270∶400∶1. 3∶2), the detection wavelength was 220 nm, the flow rate was 1. 0 ml·min-1 , the column temperature was 30 ℃ and the injection volume was 20 μl. The effects of different release apparatus, release media and rotation speeds on the release of phencynonate hydrochloride extended-release tablets were studied as well. Results:The established drug release determination method had a good linear relationship within the range of 0. 3-5. 0 μg· ml-1(r=0. 999 8), and the average recovery was 100. 6%(RSD=1. 16%, n=15). Under the conditions of 900ml pH 3. 0 phos-phate buffer solution as the release medium, rotation speed of 50 r·min-1 and the settlement basket as the apparatus, the release be-havior of the product was complied with a zero-level model in vitro, and the release equation was as follows:Q=6. 141 2t-9. 328 7(r=0. 996). Conclusion:The method is simple, accurate and reliable, and suitable for the quality control of phencynonate hydrochlo-ride extended-release tablets.

Plasma Concentration of Phencynonate Hydrochloride in Dogs by HPLC-MS/MS and Its Pharmacokinetic Study / 中国药房

OBJECTIVE:To determine the plasma concentration of Phencynonate hydrochloride(PCH)in dogs,and to calcu-late pharmacokinetic parameters. METHODS:6 Beagle dogs were given PCH tablets(2 mg and 4 mg)intragastrically. The blood samples were collected 5 min before medication and 0.17,0.25,0.5,0.75,1.0,1.25,1.5,2,3,4,6,8,10,12,14,16,18, 24 and 36 h after medication,2 ml each time. Using penehyclidine hydrochloride as internal standard,HPLC-MS/MS method was adopted to determine the plasma concentration of PCH. The medication plans were interchanged 2 weeks later. The pharmacokinetic parameters were calculated using DAS 2.0 software. RESULTS:The linear range of PCH was 0.1-15 ng/ml(r=0.999 6);the low-est limit of quantification was 0.1 ng/ml;the methodology recovery were 97.30%-103.20%;the extraction recovery were 52.30%-60.11%(RSD<11%,n=5). The main pharmacokinetic parameters of low and high doses were as follows as t1/2α of (0.678±0.525)and(0.405±0.465)h,tmax of(1.042±0.401)and(0.900±0.418)h,cmax of(14.063±6.29)and(31.580±9.673) mg/L,AUC0-36 h of(48.186±14.776)and(79.269±34.649)mg·h/L. CONCLUSIONS:The method is simple,sensitive and speci-fic,and can be used for pharmacokinetic study of PCH in dogs.