Pharmacokinetics of the S- and R-enantiomers of aminoglutethimide in saliva of breast cancer patients: Correlations with plasma

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.

Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons

“…The mechanisms of actions do not involve any known pharmacological properties of this drug and should be addressed in further investigations. Aminoglutethimide has been used for therapies of hormone‐dependent malignant tumors in the United States ( Miller et al ., 1987 ; Alshowaier et al ., 1999 ). Daily dose of aminoglutethimide is 250–1000 mg, and serum concentration of this drug in patients receiving 1000 mg dosing has been reported to be 9.0 μ g ml −1 (38.7 μ M ; Miller et al ., 1987 ).…”

“…Aminoglutethimide also inhibits aromatase, an enzyme involved in production of estrogens, with an apparent K i value of 0.6 μ M ( Salhanick, 1982 ; Foster et al ., 1983 ). On the basis of these actions, clinical use of aminoglutethimide is approved in the United States for the treatment of hormone‐dependent malignant tumors ( Miller et al ., 1987 ; Alshowaier et al ., 1999 ). Here we report unexpected findings that aminoglutethimide protects cortical neurons from excitotoxic and ischemic injuries, probably through the mechanisms unrelated to steroid biosynthesis.…”

Kristallstrukturbestimmung organischer Verbindungen mittels Röntgenbeugungsmethoden : Vergleich, Grenzen und Kombination

“…[103] Ein Enantiomer eines API kann gegen eine bestimmte Krankheit wirken, während hingegen -im schlimmsten Fall -das andere Enantiomer des gleichen API toxisch ist. [104] Erschwerend kommt hinzu, dass meist wenig (einige Mikrogramm) API für Analysen zur Verfügung stehen. Somit besteht die Nachfrage nach einer neuen Methode zur Bestimmung der absoluten Konfiguration aus Röntgenpulverdaten als Alternative zur Einkristallstrukturanalyse, für deren Einkristallzüchtung mehrere Milligramm Substanz benötigt werden.…”