METHYLPREDNISOLONE DISPOSITION IN RABBITS - ANALYSIS, PRODRUG CONVERSION, REVERSIBLE METABOLISM, AND COMPARISON WITH MAN

Abstract

Methodology was evolved for comparison of methylprednisolone [an antiinflammatory drug] disposition in man and rabbit. Methylprednisolone, methylprednisone and methylprednisolone hemisuccinate ester concentrations in plasma were measured by HPLC [high-performance liquid chromatography] methodology after i.v. administration of each compound to rabbits. Methylprednisolone hemisuccinate is rapidly and completely hydrolyzed to methylprednisolone with a half-life of 10 min. Dosing with the free alcohol or ester produces identical disposition curves for methylprednisolone. Methylprednisolone underwent rapid and reversible metabolism with methylprednisone, a phenomenon also seen in man. Plasma concentrations of methylprednisolone are appreciably greater than the metabolite regardless of the form of steroid given. Administration of the metabolite yields 67% availability of methylprednisolone. The occurrence of reversible metabolism produces an apparent clearance which is .apprx. 71% of the value of the real elimination clearance for both steroids. Man and rabbit show identical plasma protein binding of methylprednisolone (77%). Small differences in apparent clearance (man, 5.74 ml/min per kg; rabbit, 7.93 ml/min per kg) can be accounted for by the animal scale-up principle (body wt). The rabbit is thus a useful animal model for further assessing mechanisms of drug- or disease-steroid interactions which occur in man.