| Piperphentonamine Hydrochloride (PPTA) is a calcium sensitizer appealed as a class one new drug, which was researched and developmented by our country.The preclinical research indicated that it has the cardiotonic and cardioprotection effects.The main aim of this paper is to investigate the safey and pharmacokinetic action of PPTA for injection in Chinese healthy voluteers, to gain the pharmacokinetic parameters, so as to provide some recommendations for the design of the phaseⅡclinical research proposal.The preclinical research found that PPTA is a metabolic compound.Ml and M6 were the reduction products, whose structures were similar to the origin.To support the pharmacokinetic research of PPTA, a LC-MS/MS mehod for the determation of PPTA, the possible metabolites M1 and M6 in biological samples simultaneously was developed.The MS/MS was used in the methodology of biopharmaceutical analysis. Protein precipitation was utilized for the plasma preparetion ans solid phase extraction was utilized for the urine preparetion. The step mobile phase was applied:1%HAc in H2O (A), Acetonitrile (B). In 0-2min, the ratio of A:B stepped from 90:10 to 75:25. In 2-8.5min, the ratio of A:B sustained at 75:25.In 8.5-10.5min, the ratio of A:B sustained at 90:10. The total time of analysis was 10.5min, and the flow rate was 0.25mL·min-1. The MRM model was used in the data acquiring. All of the parent ions of PPTA, M1 and M6 were [M+H]+,m/z were 354,356 and 358, respectively.Both the linear range of standard curve of plasma sample of PPTA and M1 were 0.1～500 ng·mL-1,that of M6 was 0.2～500 ng·mL-1; and both the linear range of standard curve of urine sample of PPTA and M1 were 0.1～200 ng·mL-1, that of M6 was 0.2～200 ng·mL-1; and the r2>0.99.The results of toleration indicated that:there were no serious events correlated to the single dosage of 0.1,0.2,0.4,0.8,1.32,2 mg·kg-1 of PPTA. In the single dosage of 2.68 mg·kg-1,5 cases have hand anesthesia,2 cases have dizziness,1 case has ischemeic ECG In the single dosage of 2 mg·kg-1 (group 8), the ECG of two cases show T wave invert.The maxim safety dosage for single dose of PPTA was at least 1.32 mg·kg-1.The results of pharmacokinetics indicated that:after the single intravenous bolus injection of 0.2mg·kg-1,0.4mg·kg-1 and 0.6 mg·kg-1 PPTA, the main pharmacokinetic paramaters of PPTA were: the average Cmax were (11.04±11.67), (47.40±22.10) and (82.83±59.97) ng·mL-1, respectively; ti/2Z were (4.30±1.08), (5.08±1.76) and (5.27±1.11) min, respectively; AUC0-t were (131.91±82.42), (333.88±145.17) and (602.98±380.04) ng·mL-1·min, respectively; AUC0-∞were (133.43±82.51), (335.86±145.28) and (604.50±380.24) ng·mL-1·min, respectively; the total urinary recovery rates (0-24h) were(0.14±0.06), (0.10±0.05) and (0.20±0.11)%, respectively.After the single intravenous bolus injection of 0.2mg·kg-1,0.4mg·kg-1 and 0.6mg·kg-1 PPTA,the main pharmacokinetic paramaters of Ml were:the average Cmax were (78.69±27.86) (148.66±43.70) and (221.15±89.22) ng·mL-1, respectively; t1/2Z were (50.04±5.38), (57.57±9.53) and (60.09±16.06) min, respectively; AUC0-t were (2332.37±496.47), (4838.95±872.65) and (7777.17±1488.57) ng·mL-1·min, respectively; AUC0-∞were (2347.12±494.33), (4874.26±876.94) and (7844.00±1481.94) ng·mL-1·min, respectively; the total urinary recovery amount (0～24 h) were(6.38±8.10)、(37.04±59.13) and (85.75±92.20)μg, respectively. The total urinary recovery amount (0～24 h) of M6 were (5.31±3.60)、(8.20±5.32) and (18.08±6.25)μg, respectively.After the single intravenous bolus injection of PPTA 0.2～0.6 mg·kg-1, the mean Cmax and AUC were linear with the dosage(R2>0.99), there were no difference of half life among these doses, PPTA showed linear pharmacokinetic properties in these dosage rang.PPTA were extensively metabolited in the human body. In the urine, the main were phase II conjunction product. In the plasma, the main were phase I reduction products and glucuronic acid conjugates of some phase I reduction products.I completed my clinical pharmacy practice in the department of respiratory and provided pharmaceutical service mainly for asthma patients.The clinical pharmacy practice contains learning knowledge before going to the clinic, supplying drug informations, solving problems of drug treatment, founding pharmaceutical case files, provide pharmacy education to patient and so on. |
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