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This study was undertaken to examine the pharmacokinetics of both enantiomers of AG—that is, (R‐AG) and (S‐AG) and respective acetyl metabolites, R‐AcAG and S‐AcAG—in breast cancer patients. Six patients received a single dose (500 mg) of the racemic drug, and serial plasma samples and urine were collected 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 concentrations of R‐AG were about 1.5 times higher than those of S‐AG, and the data for both enantiomers exhibited the characteristics of the one‐compartment open model. There were no significant differences between R‐ and S‐AG in ka, tmax, V/F, and t1/2. The formation of R‐ and S‐AcAG was rapid, and no correlation was found between the t1/2 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 other pharmacokinetic differences observed. Both enantiomers had low renal extraction ratios, suggesting extensive tubular reabsorption of the compounds. However, based on the data obtained, it was concluded that the main factor 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.

No abstract

This study was undertaken to examine the pharmacokinetics of both enantiomers of AG—that is, (R‐AG) and (S‐AG) and respective acetyl metabolites, R‐AcAG and S‐AcAG—in breast cancer patients. Six patients received a single dose (500 mg) of the racemic drug, and serial plasma samples and urine were collected 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 concentrations of R‐AG were about 1.5 times higher than those of S‐AG, and the data for both enantiomers exhibited the characteristics of the one‐compartment open model. There were no significant differences between R‐ and S‐AG in ka, tmax, V/F, and t1/2. The formation of R‐ and S‐AcAG was rapid, and no correlation was found between the t1/2 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 other pharmacokinetic differences observed. Both enantiomers had low renal extraction ratios, suggesting extensive tubular reabsorption of the compounds. However, based on the data obtained, it was concluded that the main factor 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.