Pharmacokinetic scaling of epirubicin using allometric and species-invariant time methods
We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats. To analyze ID-6105 levels in biological samples, we used an HPLC-based method which was validated in a pharmacokinetic study by suitable criteria. The concentrations of ID-6105 after the multiple administration for 5 days were not significantly different from the results after the single administration. The t1/2alpha, t1/2beta, Vdss, and CLt after the multiple administration were not significantly different from the values after the single administration. Moreover, the concentrations of ID-6105 1 min at day 1-5 after i.v. bolus multiple administration did not show the significant difference. Of the various tissues, ID-6105 mainly distributed to the kidney, lung, spleen, adrenal gland, and liver after i.v. bolus multiple administration. ID-6105 concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration decreased to low levels. ID-6105 was excreted largely in the bile after i.v. bolus multiple administration at the dose of 3 mg/kg. The amounts of ID-6105 found in the bile by 12 h or in the urine by 48 h after the administration were calculated to be 14.1% or 4.55% of the initial dose, respectively, indicating that ID-6105 is mostly excreted in the bile. In conclusion, ID-6105 was rapidly cleared from the blood and transferred to tissues, suggesting that ID-6105 might not be accumulated in the blood following i.v. bolus multiple dosages of 3 mg/kg every 24 h for 5 days. By 48 h after i.v. bolus administration, ID-6105 concentrations in various tissues had decreased to very low levels. The majority of ID-6105 appears to be excreted in the bile.