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Pharmacokinetics of prednisolone and its local anti-inflammatory steroid-21-oate ester derivatives. In vitro and in vivo comparative study.

A new class of local anti-inflammatory steroid-21-oate esters synthesized by modifying the ketol side chain of prednisolone was found to exhibit minimal systemic side effects such as pituitary-adrenal suppression. It has been hypothesized that the absence of the systemic toxicities of these steroids is due to the rapid hydrolysis of the carboxylate ester group to inactive and readily excretable acid metabolites. The pharmacokinetics of prednisolone and its two ester derivatives, methyl 20 alpha- and 20 beta-dihydroprednisolonate (P4 alpha and P4 beta), were studied in rats following im administration of doses ranging from 0.5 to 10 mg/kg. The absorption of each of the three compounds was rapid, as the peak concentration was attained within 20 min after injection. The elimination half-lives of P4 alpha, P4 beta, and prednisolone were independent of dose and were 1.12, 0.28, and 0.53 hr at 10 mg/kg doses, respectively. The AUCs of P4 alpha, P4 beta, and prednisolone following a 10 mg/kg dose were 7678, 242, and 3037 ng/ml.hr, respectively. The pharmacokinetics of the P4 alpha were linear as the AUC increased proportionally with dose. An in vitro study showed that P4 beta was approximately 100% hydrolyzed within 1 hr in plasma at 37 degrees C, whereas P4 alpha was about 30%. However, a negligible disappearance of prednisolone occurred in vitro over a period of more than 2 days. These results suggest that the minimal systemic side effects of these new steroids may be ascribed to the differences in their pharmacokinetic profiles and metabolism from those of prednisolone.