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 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.

A prospective study of VEC-POB and POCE chemotherapy in aggressive non-Hodgkin's lymphoma.

The optimal combination and scheduling of chemotherapy for aggressive non-Hodgkin's lymphoma is unclear, and the elderly have a poor tolerance to treatment. A Phase II prospective study was undertaken using outpatient weekly combination chemotherapy: the VEC-POB (etoposide, epirubicin, cyclophosphamide, cisplatin, Oncovin, bleomycin, and prednisone) regimen in patients < 60 years and less intensive POCE (etoposide, Oncovin, cyclophosphamide, and epirubicin) in patients > or = 60 years. All patients with intermediate and high-grade lymphoma (International Working Formulation) with bulky disease and/or advanced stages (III, IV) seen between January 1991 and June 1992 were entered. Of 29 patients treated with VEC-POB, 23 patients (79%) achieved complete remission (CR), with one (3%) toxic death. Overall survival at 29 months is 67%, and disease-free survival at 60 months is 60%. Of 29 patients treated with POCE, 14 achieved CR, with three (10%) toxic deaths. Overall survival is 58% at 18 months, and disease-free survival at 10 months is 50%. Adverse prognostic factors were analyzed. The results are comparable to the best results achieved with other regimens, and toxicity is acceptable.