Methylprednisolone disposition in rabbits. Analysis, prodrug conversion, reversible metabolism, and comparison with...

Methodology was evolved for comparison of methylprednisolone disposition in man and rabbit. Methylprednisolone, methylprednisone, and methylprednisolone hemisuccinate ester concentrations in plasma were measured by HPLC methodology after iv 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 was found to undergo 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 about 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/kg; rabbit, 7.93 ml/min/kg) can be accounted for by the animal scale-up principle (body weight0.89). The rabbit is thus a useful animal model for further assessing mechanisms of drug- or disease-steroid interactions which occur in man.