EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1987, Vol. 12, No I, pp. 49-57 Troleandomycin effects on methylprednisolone and methylprednisone interconversion and disposition in the rabbit WILLIAM F. EBLING, STEVEN A. RICH, STANLEY J. SZEFLER* and WILLIAM J. JUSKO Departments of Pharmaceutics. Pharmacology and Therapeutics, and Pediatrics, Schools of Pharmacy and Medicine. State University of New York at Buffalo. Buffalo. NY U.S.A. Received for publication: June II, 1986 Key Words: Troleandomycin, Methylprednisolone, Pharmacokinetics, Rabbits, Drug Interaction SUMMARY A study of the effects of troleandomycin (TAO) on the disposition of intravenous methylprednisolone in rabbits was performed in order to develop an animal model to further evaluate the mechanism of TAO/steroid beneficial effects in severe asthma. The plasma concentration-time profiles of methylprednisolone and.methylprednisone were determined in the presence and absence of single and multiple dose TAO regimens. Pharmacokinetic analysis revealed a significant decrease in total plasma clearance of methylprednisolone in the presence of multiple dose TAO. Alterations in the disposition of the reversible metabolite, methylprednisone, were also observed. The TAO-methylprednisolone interaction may involve decreasing the degree of interconversion between the steroid and its reversible metabolite. TAO also decreases metabolite turnover more than three-fold. The antibiotic does not cause marked deviation from linear biexponential elimination of methylprednisolone as observed in man. The rabbit may serve as a useful animal model for further studies of the TAO/methylprednisolone interaction. INTRODUCTION Troleandomycin (TAO) is a macrolide antibiotic that has been recognized as a useful adjunctive agent in the treatment of severe corticosteroid dependent asthma (1-4). Clinical improvement is frequently observed when this antibiotic is added to the regimen of these patients. Such therapy often facilitates a reduction in steroid dose with an occasional reversal in steroid related side effects (5). Methylprednisolone is the synthetic steroid which, when administered concomitantly with TAO, results in the greatest "steroid sparing effect" (3). Investigation into the underlying mechanism of action has ensued. Transient, reversible abnormalities of liver function tests (6) and histologic changes compatible with liver dysfunction in some patients * Present Address: Department of Pediatrics, National Jewish Hospital and Research Center, Denver, CO 80206. Send reprint requests to: Dr. William J. Jusko, Cooke Hall 319, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260. on TAO therapy (1) have been reported. A pharmaco- kinetic evaluation of asthmatic patients revealed that TAO caused a significant decrease in plasma clearance of methylprednisolone with a corresponding increase in half-life (5). Thus, a primary consideration for this "steroid sparing effect" of TAO is an alteration in methylprednisolone disposition. The reported hepatotoxic properties of TAO (6) limits the use of normal human volunteers in the investigation of the TAO/methylprednisolone in- teraction. An animal model for studying the in- teraction is desirable. Similar disposition and plasma protein binding of methylprednisolone in man and rabbit have been reported elsewhere (7-9). We examined the rabbit as a potential model for further investigations of the interaction between these two agents. METHODS Posology Four New Zealand White rabbits with weights ranging from 4 to 5.5 kg were used in this study. The