Study Pharmacokinetics And Metabolism Of Bicalutamide And Enalapril

Bicalutamide is a nonsteroidal pure antiandrogen. It is used at a dosage of 50 mg once daily in combination with a luteinizing hormone-releasing hormone analogue or surgical castration for the treatement of advanced prostate cancer. Enalapril maleate is an angiotensinⅡ-converting enzyme inhibitor for the treatment of hypertension clinically. The study was on the basis of bicalutamide and enalapril maleate. The pharmacokinetics and metabolism of them in vivo were investigated in the present study.1. The pharmacokinetics of bicalutamide tablets in Chinese healthy volunteersA HPLC method for the determination of bicalutamide in human plasma was developed. The chromatographic conditions were as follows:Column-Zorbax SB C18, mobile phase-acetonitrile: water(45:55, v/v), extraction solvent-ethylether:dichloromethane(2:1, v/v). The chlorzoxazone was used as internal standard. The LLOQ of the method was 20.0 ng/mL. There was a good linear relationship for bicalutamide within the range of 20.0-1500 ng/mL. The method was validated to be suitable for the determination of bicalutamide in human plasma.40 healthy male volunteers were randomly divided into two groups and administrated 50 mg bicalutamide tablets in a one period parallel design test. The plasma concentrations were determined and the main pharmacokinetic parameters were calculated. The results of statistic analysis show that the reference preparation and the test preparation are bioequivalent.2. Study on the metabolism of bicalutamideMetabolites of bicalutamide in rat、dog、microbial modal and human were investigated by LC/MSn method. A total of 11 metabolites were found, among which 4 metabolites were known, 7 metabolites were novel. The metabolites were identified by their ESI-MS spectra, MS/MS spectra, chromatographic behaviors and polarity between metabolites as well as comparing to bicalutamide. The metabolites included hydroxyl-bicalutamide (RM1-RM7, RM7 is dihydroxyl-bicalutamide), carboxylic acid cleaving at the amide (RM8), glucuronide conjugate of bicalutamide (RM9), glucuronide conjugates of hydroxyl-bicalutamide (RM10 and RM11). The major metabolic pathways of bicalutamide in vivo were hydroxylation、hydrolysis at the amide and glucuronide conjugation. Secondary metabolism via these pathways was also evidenced.3. The pharmacokinetics of enalapril meleate tablets in Chinese healthy volunteersA LC/MS/MS method was developed to determine the plasma concentrations of enalapril and enalaprilat. The chromatographic conditions were as follows:Column-Zorbax Extend C18, mobile phase-methanol:water:formic acid(70:30:0.2, v/v/v), extraction solvent-acetoacetate: isopropyl alcohol(95:5, v/v). The daidzein was used as internal standard. Select reaction monitoring (SRM) with the precursor to product ion combinations of m/z 377→m/z 234, m/z 349→m/z 206 and m/z 255→m/z 199 were used to quantify enalapril, enalaprilat and daidzein (IS), respectively. The LLOQ of the method was 0.1 ng/mL. There was a good linear relationship for both enalapril and enalaprilat within the range of 0.1～100 ng/mL. The method was validated to be suitable for the determination of enalapril and enalaprilat in human plasma. A randomized, cross-over and self-control clinical trail enrolled 18 healthy male volunteers. The plasma concentrations of enalapril and enalaprilat were determined and the main pharmacokinetic parameters were calculated. The results of statistic analysis show that the reference preparation and the test preparation are bioequivalent.