Kinetics of methylprednisolone and its hemisuccinate ester Methylprednisolonein the form of its hemisuccinate ester was injected intravenously in doses of 10 mgl kg and 63.1 mg. Plasma levels of methylprednisolone and of the ester were measured and their kinetics were calculated. Results indicate dose dependency in the kinetics of both. About 10%of the dose was excreted unchanged as hemisuccinate in the urine, indicating incomplete conversion of the prodrug. When methylprednisolone (80 mg) was also taken by mouth, the relative bioavailabilityof the tablets was 99%. Saliva levels of rnethylprednisolone were low but paralleled plasma levels in the postdistribution phase. No rnethylprednisolone hemisuccinate was found in saliva. (CLIN PHARMACOL THER 37:502-507,1985.) Hartmut Derendorf, Ph.D., Helmut Mollmann, M.D., Peter Rohdewald, Ph.D., Jorg Rehder, B.S., and Ernst Wilhelrn Schmidt, M.D. Gainesville, Fla., and Bochum and Miimter, West Gemany The use of glucocorticoids in high doses has been recommended for shock, but because they are poorly soluble in water, they cannot be injected intravenously. Esterification of the glucocorticoid alcohols with acids such as succinic acid and phosphoric acid results in water-soluble derivatives of the steroid that can be in- jected intravenously. These esters supposedly hydro- lyze rapidly in the body to release the free corticoid alcohols. One of the most common glucocorticoid esters is rnethylprednisolonehemisuccinate. Relatively little in- formation on its kinetics is available. In contrast to an earlier report of prednisolone kinetics that shows non- linear it^,^ the only recent study of high-dose methyl- prednisolone kinetics6 reported that the drug follows linear kinetics. Our purpose was to follow the kinet- ics of rnethylprednisolone and of methylprednisolone hemisuccinate after high- and low-dose intravenous injections of the ester. Methylprednisolone kinetics af- ter oral dosing with the alcohol were also studied, and urine and saliva samples were assayed. METHODS Our subjects were 11 men and six women with an average age of 32 years (range 23 to 47 years) and an From the College of Pharmacy, University of Florida, Gainesville; Medicinal Clinic, University of Bochum, Bochum; and Institute of Pharmaceutical Chemistry, University of Miinster, Miinster. Received for publication July 26, 1984; accepted Dec. 19, 1984. Reprint requests to: Dr. Hartmut Derendorf, Box 5-4, College of Pharmacy, University of Florida, Gainesville, FL 32610. 502 average weight of 77 kg (range 57 to 100 kg). In a chronic study, one subject with lung fibrosis received methylprednisolone for 29 days. The drug was dosed in three different methods: (1) A high-dose intravenous injection of 10 mg/kg methylprednisolone as its hemi- succinate (n = lo), (2) a low-dose intravenous injec- tion of 80 mg rnethylprednisolone hemisuccinate (n = 1I); and (3) an oral dose of 80 mg methylprednisolone (n = 9). Blood samples were drawn immediately be- fore dosing and at appropriate points up to 24 hours after dosing. Blood was centrifuged and plasma was separated. Samples were frozen immediately and stored at - 20" C until analyzed. Urine was collected and aliquots were frozen until analyzed. Saliva was col- lected without stimulation for 3 to 4 minutes after dos- ing and was frozen until analyzed. One subject received 80 mg iv methylprednisolone hemisuccinate at 8 AM and 40 mg iv at 8 PM for 6 days. Blood was drawn immediately before and 10 minutes after the injection. This subject also received doxycy- cline, dihydrocodeine, oxazepam, and an antacid. The subject was given rnethylprednisoloneorally for 23 days (11 daysof 80mgat 8 ~~and40mgat ~PM, and 12 days of 40 mg at 8 AM and 20 mg at 8 PM). Samples were assayed for methylprednisolone, methylprednis- olone hemisuccinate, and endogenous hydrocortisone by an HPLC meth~d.~ RESULTS Method 1. After intravenous injection of high doses of methylprednisolone hemisuccinate, the ester con-