Determination and pharmacokinetic study of oxymatrine and its metabolite matrine in human plasma by liquid chromatography tandem mass spectrometry

There is little information about the pharmacokinetics of oxymatrine (OMT) and its metabolite matrine (MT) after i.v. administration of OMT in human. Therefore a specific and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the determination and pharmacokinetic study of OMT and its metabolite MT in human plasma after i.v. infusion administration of 600 mg of OMT in 100 ml of 5% glucose injection in 0.5 h. The analysis was carried out on a Lichrospher-CN column (250 mm x 4.6 mm, i.d., 5 mu m, Merck) with mobile phase of methanol-ammonium acetate (20 mmol/l; 85:15, v/v) pumped at a flow rate of 1.0 ml/min. The tandem mass detection was made with electrospray ionization in positive ion selected reaction monitoring mode, with argon collision-induced dissociation ion transitions m/z 265.2 to m/z 265.2 for OMT at 25 eV, m/z 249.2 to m/z 249.2 for MT at 25 eV and m/z 340.2 to m/z 324.0 at 35 eV for the internal standard (papaverine), respectively. The assay was validated to be accurate and precise for the analysis in the concentration range of 1.0-40,000 ng/ml for both OMT and NIT with the LOD being 0.5 and 0.2 ng/ml, respectively, when 0.25 ml of human plasma sample was processed with papaverine as internal standard. The pharmacokinetic study was made with 10 healthy male Chinese subjects. The plasma concentration time profiles of OMT and MT obtained were best fitted with two-compartment and one-compartment models, respectively. The main pharmacokinetic parameters found for OMT and NIT after i.v. infusion were as follows: C-max (20,519 +/- 1758 1) and (247 +/- 45) ng/ml, T-max (0.5 +/- 0.1) and (5.6 +/- 1.7) h, AUC(0-1) (20,360 +/- 5205) and (3817 +/- 610) ng h/ml, AUC(0-infinity) (20,436 +/- 5188) and (3841 +/- 615) ng h/ml, t(1/2) (2.17 +/- 0.49) and (9.43 +/- 0.62) h, respectively. The CL/F and V-d/F of OMT were (43.8 +/- 10.8) l h(-1) and (70.1 +/- 26.6) l, respectively. Therefore only a small amount of OMT was reduced to NIT following i.v. administration of OMT judged by the AUCs. (c) 2006 Elsevier B.V. All rights reserved.