Pharmacokinetics of HZ08 in rats by liquid chromatography-tandem mass spectrometry

A selective and sensitive liquid chromatographic method coupled with ion spray tandem mass spectrometry detection (LC-MS/MS) was developed for the determination and pharmacokinetic study of N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08, a candidate reversing agent for multidrug resistance of cancer) liposome injection in rat plasma. The analyte was extracted from plasma using liquid-liquid extraction by methyl tert-butyl ether with drotaverine as internal standard. The chromatographic separation was performed on a Kromasil-C18 column (150 mm x 4.6 mm, i.d., 5 microm) with gradient elution. The tandem mass detection was made with electrospray ionization in positive ion selected reaction monitoring mode with argon collision-induced dissociation. The ion transitions were m/z 523.1 to 342.1 for HZ08 at 27eV and m/z 398.1 to 326.1 at 35eV for the internal standard, respectively. The determination was validated to be accurate and precise for the analysis in the concentration range of 5-10,000 ng/ml for HZ08 with the lower limit of detection (LOD) being 1 ng/ml, when 0.1 ml of rat plasma sample was processed. The main pharmacokinetic parameters found for HZ08 after intravenous (i.v.) administration of its liposome injection at doses of 2, 4 and 8 mg/kg were as follows: C(max) (4511+/-681), (5553+/-1600) and (6444+/-950) ng/ml, T(max) (0.033+/-0), (0.056+/-0.048) and (0.033+/-0) h, t(1/2) (1.75+/-0.19), (1.63+/-0.12) and (1.56+/-0.18) h, AUC(0-6) (899+/-112), (1238+/-190) and (1707+/-307) h ng/ml, AUC(0-infinity) (917+/-110), (1256+/-189) and (1723+/-306) h ng/ml, MRT (1.14+/-0.21), (1.01+/-0.13) and (1.16+/-0.17) h, CL (2.90+/-0.15), (3.01+/-0.74) and (4.11+/-0.59)l/h/kg, respectively. The plasma concentration-time profiles of HZ08 were best fitted with two-compartment models. Linear pharmacokinetics was found for HZ08 in rats after intravenous administration of the liposome injection.