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 (150mm x 4.6mm, i.d., 5 mu m) 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 mlz 523.1 to 342.1 for HZ08 at 27 eV and mlz 398.1 to 326.1 at 35 eV 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 I 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) 1/hlkg, 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. (C) 2007 Elsevier B.V. All rights reserved.