Hepatic Enzyme Induction with Phenobarbital and Doxorubicin Metabolism and Myelotoxicity in the Rabbit

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Abstract
Doxorubicin (DOX) undergoes extensive liver metabolism. This study was designed to compare the pharmacokinetic and myelotoxicity profiles of DOX and metabolites with and without phenobarbital-associated hepatic enzyme induction. DOX was administered i.v. to eight rabbits with and without 7 prior days of oral phenobarbital, with venous blood samples collected between 0 and 72 hr for determination of plasma DOX and metabolite concentrations by high-performance liquid chromatography and complete blood counts obtained on days 1, 5, 7, 8, and 9. DOX AUC∞ t1/2β and CLT values were significantly reduced by phenobarbital induction (FBI), while only the formation clearance of DOX metabolites was significantly changed. PBI had no effect on nadir neutrophil counts but was associated with significantly accelerated neutrophil recovery. Hepatic enzyme induction with phenobarbital significantly reduces plasma DOX exposure while increasing the rate of metabolite formation. These effects result in significant acceleration of neutrophil recovery.