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 phase II trial of circadian-timed paclitaxel and cisplatin therapy in metastatic breast cancer.

PURPOSE: In a phase II study with combination paclitaxel and cisplatin in metastatic breast cancer using circadian timing, we attempted to maximise response and minimise toxicity. MATERIALS AND METHODS: Forty-one patients with histologically-proven metastatic breast cancer with or without previous chemotherapy were treated with Paclitaxel 135 mg/m2 administered as a three-hour infusion at 06.00 hours followed by cisplatin 75 mg/m2 as a one-hour infusion at 18.00 hours utilising circadian timing. Six cycles were planned once every 21 days. Response assessment was performed every two cycles, and toxicity was measured using WHO criteria. RESULTS: All patients were evaluable for response and toxicity. There were nine (22%) complete responses (CR), and 24 (59%) partial responses (PR), for an overall response rate of 80% (95% confidence interval (CI) 69-92). Responses were seen in patients previously treated with anthracyclines (75%) (95% CI 57-92), and in patients who had had no prior chemotherapy (90%) (95% CI 71-100). Responses were seen in all metastatic sites: liver 80%, lung 76%, bone 69%, and soft tissues 71%. The overall median response duration was seven months (range 3-26, 95% CI 5.0-9.8), and 14 of the responses (42%), (95% CI 28-62) were durable. A total of 212 cycles of chemotherapy were given. There were 15 episodes (7%) of grade 3-4 neutropenia, seven (3.2%) of grade 3-4 neurologic toxicity, and three (1.4%) of grade 3-4 nephrotoxicity. There were no toxic deaths. CONCLUSION: The combination of paclitaxel and cisplatin is very effective in metastatic breast cancer, and with application of circadian timing, toxicity has been acceptable. This combination is being tested as primary therapy in locally-advanced breast cancer at our institution.

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.

Liquid chromatographic separation and measurement of optical isomers of aminoglutethimide and its acetyl metabolite in plasma, saliva, and urine.

An accurate and specific liquid chromatographic method for the separation and analysis of the R(+) and S(-) enantiomers of both aminoglutethimide (AG) and its acetylated metabolite (AcAG) in plasma, saliva, and urine is described. The separation was achieved by use of two serial Chiralcel OD columns [cellulose tris(3,5-dimethylphenyl carbamate)] with a mixture of hexane/isopropanol/methanol (65:17.5:17.5, per volume) as a mobile phase. The flow rate was 0.7 ml/min, and the compounds were detected in the effluent spectrophotometrically at 245 nm. The plasma, saliva, or urine sample (300 microliters) was extracted with dichloromethane after the addition of an equal volume of acetate buffer (pH 5.6) to the sample. The extraction recovery of the R(+) and S(-) enantiomers of AG and AcAG from plasma, saliva, and urine at different concentrations under these conditions was > 80.9%. No interference from any endogenous substance or concomitantly used drug was observed. The ratio of the peak area of R(+) and S(-) enantiomers of both AG and AcAG/internal standard was linearly (r > or = 0.995) related to concentration in the range 0.83-40.0 micrograms/ml, and the coefficient of variation (CV) at different concentrations was consistently < or = 13%. We are presently employing this method to study the pharmacokinetics of each of these enantiomers in breast cancer patients.