ALTERATIONS IN THE PHARMACOKINETICS AND PROTEIN-BINDING OF ENPROFYLLINE IN EISAI HYPERBILIRUBINEMIC RATS

Mutant rats possessing conjugated hyperbilirubinemia have recently bee n established from Sprague-Dawley rats (SDRs) and are called Eisai hyp erbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of enprofyl line, which is mainly excreted into the urine by an active tubular sec retion mechanism, were investigated in 9- and 19-week-old EHBRs and co mpared with their age-matched normal SDRs. Enprofylline was administer ed intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetic s. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. Both systemic clearance a nd volume of distribution at steady state of enprofylline significantl y increased in 19-week-old EHBRs. However, there were no differences i n the glomerular filtration rate estimated as inulin clearance and fra ction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia i n EHBRs had no effect on the pharmacokinetics and renal handling of un bound enprofylline. These results indicate that the pharmacokinetics o f enprofylline, but not renal handing, glomerular filtration, or tubul ar secretion are modified in EHBRs by changes in protein binding behav ior.