A general method for the assay of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors lovastatin, pravastatin, and simvastatin in plasma has been developed and validated. The analytes are isolated from plasma by a solid-phase extraction procedure which separates the lactone and acid forms of the drugs. The lactone is converted to the acid form, which is subsequently derivatized by pentafluorobenzylation of the carboxyl group, and trimethylsilylation of the hydroxyl functions. Derivatized samples of intrinsic and converted acid are assayed by gas chromatography/mass spectrometry using negative chemical ionization mass spectrometry. The method has sufficient sensitivity, precision, accuracy, and selectivity for the analysis of clinical samples containing the drugs administered at therapeutic doses. The method thus permits determination of both the lactone and hydroxy acid forms of lovastatin and simvastatin, and is also applicable to the assay of pravastatin.

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