RESUMEN
Objective: To evaluate the toxicokinetics and in vivo accumulation of norcantharidin lipid microsphere for injection (NCTD-LM) in Beagle's dogs following 90 d repeated iv administration by comparing with sodium demethylcantharidate injection (NCTD-I). Methods: An ultra high performance liquid chromatography-tandem mass spectrum method was employed to determine the NCTD in plasma of Beagle's dog after 1, 44, and 90 d repeated iv administration. The toxicokinetic parameters were calculated from the plasma concentration. Results: After the first iv administration of 0.8, 1.6, and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC0-t were (2.22 ± 0.53), (4.77 ± 1.13), and (13.43 ± 3.64) h∙mg/L, respectively, while the t1/2 were (1.37 ± 0.18), (1.64 ± 0.42), and (1.98 ± 0.25) h, respectively. After the 90 d repeated iv administration of 0.8, 1.6 and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC0-t were (3.58 ± 0.95), (11.4 ± 2.0), and (23.5 ± 3.9) h·mg/L, respectively, while the t1/2 were (3.87 ± 1.90), (5.75 ± 3.29), and (5.84 ± 2.45) h, respectively. For NCTD-I, the AUC0-t were (9.07 ± 2.09) and (14.1 ± 3.0) h∙mg/L respectively after 1 and 90 d repeated iv administration, while the t1/2 were (2.84 ± 1.34) and (3.53 ± 1.26) h. 15 and 30 d after the end of administration, the concentration of NCTD in plasma of Beagle's dog in each group were all dropped below the lowest limit of quantification (LLOQ). Conclusion: NCTD displays a nonlinear elimination at the dose range of 0.8-3.2 mg/kg after iv administration of NCTD-LM to Beagle's dog. Over the 90 d repeated iv administration period, the plasma concentration levels, AUC0-t, and t1/2 for both NCTD-LM and NCTD-I are increased with time increasing. However, no accumulation of NCTD is observed for the both formulations.
RESUMEN
OBJECTIVE: To provide a method for calculating mean residence time of drugs in central compartment (MRTC).