The Study On Preclinical Pharmacokinetics Of Peperphentonamine

Peperphentonamine, as a novel compound being synthesized for the first time, has been verified to have the effect of extent cardiac stimulant and vascular dilatation in many vitro and vivo models. The works of this paper was designed to evaluating the metabolism and pharmacokinetic features of peperphentonamine in animals, so as to support the metabolism and pharmacokinetic study in human and offer the reference for clinical dosage.1. The establishment of analytical method of peperphentonamine in biological matrixA high performance liquid chromatography method in possession of speciality, stability and extent linear range was developed to determine peperphentonamine in biological matrix, peperphentonamine and the internal standard diazepam were extracted by ethyl acetate from matrix and separated by a SymmetryShisld?RP18 column (3.9+150 mm, Waters Corporation) with UV detection wavelength at 330 nm. A gradient mobile phase of methanol, acetonitrile and 50mmol/L phosphoric acid buffer (pH 2.8) was run at a flow rate of 1 mL/min. A Good linearity was obtained over the plasma concentration range 8-20000ng/mL of peperphentonamine with correlation coefficient from 0.9964 to 0.9986 when applying the weighted least-squares method and the limit of quantitative was 8 ng/mL. The precision of intra-assay and inter-assay was evaluated by analysis of variance with the result of 4.5-9.6% and 10.8-13.2%, respectively. The average extraction recovery was 70.2%.2. The pharmacokinetics study of peperphentonamine in animalFollowing a single intravenous administration with different dose of peperphentonamine to rats (2, 4 and 8 mg/kg), beagle dogs (2.63, 5 and 10 mg/kg)and an infusion administrtion to monkey at the dose of 2.8 mg/kg, the blood samples were collected at different time after dosing. All collected blood samples were centrifuged to obtain plasma and the concentration of peperphentonamine in plasma were determined by HPLC method described as above. Pharmacokinetic parameter calculations and pharmacokinetic modeling were carried out using the 3p97 pharmacokinetics software edited by mathematics pharmacology council of Chinese pharmaceutical committee. It was shown that the plasma concentration-time data was fit to a single compartment pharmacokinetic model in rats after iv administration and the elimination of peperphentonamine was found to be in accord with non-linear kinetics characteristics. As regard beagle dogs it was shown that the plasma concentration-time data was fit to two-compartment pharmacokinetic model after iv administration and the elimination of peperphentonamine exhibited first order kinetic characteristics.3. The tissue distribution study of peperphentonamine in ratsRats were serially euthanized by spondylopathy luxation at 2, 6, 12, 30 min after iv administration (4 mg/kg). Tissues were taken out and made into 25% homogenate preparation with 50 mmol/L phosphoric acid buffer (pH 2.8) and the concentration of peperphentonamine in the tissues were determined by HPLC method. It was shown that peperphentonamine was distributed to the entire organism rapidly after iv administration and the concentration of peperphentonamine in plasma fell more quicker than in tissue. Two minutes after iv administration, the highest concentration of peperphentonamine was found in the lung and kidney with the next highest concentration in intestinal and plasma. But at twelve minutes after dosing, the lowest concentration of peperphentonamine was plasma and the highest concentration of peperphentonamine was lung. The drug seems not accumulate in rat.4. Urinary, fecal and biliary excretion of peperphentonamine after iv administrationBile, urine and feces of rats were collected after iv administration (4 mg/kg), then the concentration of peperphentonamine were determined by HPLC method. Itwas shown that about 1.73% of the dosage was excreted in bile and 0.08% in urine and about 90% of excretion presented within 1 h after dosing. The unchanged compound was not obser...