Pharmacokinetics of doxorubicin and its metabolite doxorubicinol in rabbits with induced acid and alkaline urine

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Abstract
The pharmacokinetics of doxorubicin in rabbits preloaded either with ammonium chloride or sodium hydrogencarbonate have been investigated following single IV administration of 5 mg/kg. Plasma samples and urine collections were obtained over 3 h following administratio, and were assayed in duplicate for doxorubicin and its main metabolite doxorubicinol by reversed-phase high-pressure liquid chromatography. The plasma concentration of doxorubicin was fitted to an open two-compartment model. The areas under the plasma concentration-time curves (AUC) of doxorubicin in rabbits with alkaline urine were approximately half the areas in rabbits with acid urine. A pharmacokinetic analysis indicated an increase in the central volume of distribution, which is interpreted as an increase in tissue permeability in the alkaline state, due to the acid-base properties of the doxorubicin molecule. The renal excretion of doxorubicin and doxorubicinol was quantitatively similar in the two groups of rabbits. The total renal excretion of anthracyclines during the experiment was calculated to approximately 6% of the administered dose. The clearances of doxorubicin were initially three times higher than inulin clearance, but approximated this value at the end of the experiment. The renal handling of doxorubicin in the rabbits is explained by glomerular filtration followed by tubular secretion and finally by a reabsorption mechanism with limited capacity.