The metabolism of the synthetic progestin, [3H]medroxyprogesterone acetate (MPA), was studied in women using a single injection technique. Computer-implemented analysis was used to calculate the MCR (MCRMPA) and volume of distribution (VoMPA) from the steroid disappearance curve. The value of an objective curve-fitting technique was demonstrated. The effect of protocol design (number and frequency of samples) on these metabolic parameters was evaluated. The estimation of VoMPA was most sensitive to alterations of experimental design and biological variability, while MCR was less easily effected. The MCRMPA of 1668 +/- 146 (SEM) liters/day was lower than that for progesterone but higher than that of another synthetic steroid, dexamethasone. Treatment of women with MPA or aminoglutethimide, two drugs known to increase the rates of testosterone and dexamethasone metabolism, respectively, did not alter MCRMPA. From these observations we conclude 1) with the single injection technique it is difficult to estimate Vo of compounds such as MPA which are rapidly metabolized and 2) the MCRMPA was higher than expected and less susceptible to drug-induced changes than the clearance of other steroids.