Pharmacokinetics of S- and R-enantiomers of aminoglutethimide following oral administration of racemic drug in breast cancer patients

This study was undertaken to examine the pharmacokinetics of both enantiome rs of AG-that is, (R-AG) and (S-AG) and respective acetyl metabolites, R-Ac AG and S-AcAG-in breast cancer patients. Six patients received a single dos e (500 mg) of the racemic drug, and serial plasma samples and urine were co llected over a 48-hour period. R-AG, S-AG, R-AcAG, and S-AcAg were measured simultaneously by high-performance liquid chromatography using two serial chiral separation columns with ultraviolet detection. The plasma concentrat ions of R-AG were about 1.5 times higher than those of S-AG, and the data f or both enantiomers exhibited the characteristics of the one-compartment op en model. There were no significant differences between R- and S-AG in k(a) , t(max), V/F and t(1/2). The formation of R- and S-AcAG was rapid, and no correlation was found between the t(1/2) values of the AG enantiomers with that of their acetylated metabolites. Overall, 41% of the dose was excreted in urine as AG (15% R-AG and 26% S-AG) and 5.1% as AcAG (2.9% R-AcAG and 2 .2 % S-AcAG). Renal clearance of S-AG was significantly greater (i.e., 2.3- fold) than that of R-AG and appears to be most likely the cause for the oth er pharmacokinetic differences observed. Both enantiomers had low renal ext raction ra ties, suggesting extensive tubular reabsorption of the compounds . However, based on the data obtained, it was concluded that the main facto r contributing to the therapeutic effectiveness of racemic AG is the large potency difference between the R- and S- forms (R > S). The pharmacokinetic differences between R-AG and S-AG appear to contribute only marginally to the activity of this drug as an aromatase inhibitor.