The pharmacokinetics of methylprednisolone and two methylprednisolone esters, the phosphate and the hemisuccinate, were investigated after intravenous administration of the esters to 12 healthy male subjects in two different doses (250 and 1000 mg). Methylprednisolone was formed more rapidly from phosphate than from hemisuccinate. During the first 30 min methylprednisolone levels were three to four times higher after phosphate administration than after hemisuccinate. The mean residence time of the hemisuccinate was significantly longer and the total-body clearance lower than those of the phosphate. Whereas very little of the phosphate (mean, 1.7%) was eliminated unchanged into the urine, there were significant amounts of hemisuccinate (mean, 14.7%) excreted renally and therefore not bioavailable. Methylprednisolone saliva levels paralleled plasma levels; the average saliva/plasma ratio was 0.22. Neither phosphate nor hemisuccinate could be detected in saliva. An average of 7.2% of the administered dose was eliminated in the form of methylprednisolone in urine. Renal clearance was 24 ml/min and not dose or prodrug dependent. For both doses endogenous hydrocortisone levels were lowered after 24 hr. For the 1000-mg dose the depression was still significant after 48 hr. The results indicate that methylprednisolone phosphate results in a faster and more efficient conversion to its active form, methylprednisolone, than methylprednisolone hemisuccinate.