PILOT-STUDY OF THE PHARMACOKINETICS OF METHYLPREDNISOLONE AFTER SINGLE AND MULTIPLE INTRAVENOUS DOSES OF METHYLPREDNISOLONE SODIUM SUCCINATE AND METHYLPREDNISOLONE SULEPTANATE TO HEALTHY-VOLUNTEERS

The pharmacokinetics of methylprednisolone were evaluated in 29 health y volunteers after multiple intravenous doses of methylprednisolone so dium succinate or the novel prodrug, methylprednisolone suleptanate. S ubjects were assigned randomly to one of four treatment groups (40, 10 0, 250, or 500 mg) and then randomly assigned to receive either the so dium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylpredniso lone and unchanged prodrug using HPLC methods. Methylprednisolone phar macokinetics exhibited both a dose and time dependency, which was simi lar for administration of both prodrugs. After first-dose administrati on, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/ hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester, After multiple dosing, mean cle arance values increased from 31.1 to 44.7 L/hr for sodium succinate do sing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent syst emic clearance values determined after multiple dosing were 1.5- to 1. 8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These dat a suggest that the dose dependency of methylprednisolone pharmacokinet ics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone meta bolism. Based on comparison of methylprednisolone pharmacokinetic para meters derived for each prodrug, methylprednisolone suleptanate result ed in a faster and slightly more efficient conversion to methylprednis olone than methylprednisolone sodium succinate.