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 × 4.6 mm, i.d., 5 μm) 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 27 eV and m/z 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 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: Cmax (4511 ± 681), (5553 ± 1600) and (6444 ± 950) ng/ml, Tmax (0.033 ± 0), (0.056 ± 0.048) and (0.033 ± 0) h, t1/2 (1.75 ± 0.19), (1.63 ± 0.12) and (1.56 ± 0.18) h, AUC0–6 (899 ± 112), (1238 ± 190) and (1707 ± 307) h ng/ml, AUC0-∞ (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.