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Pravastatin sodium (PV) is a potent cholesterol-lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Biotransformation profiles of PV in pooled human urine, plasma, and feces from healthy male volunteers given single 19.2-mg oral or 9.9-mg iv doses of [14C]PV were determined by HPLC. The predominant drug-related component in urine, plasma, and feces corresponded to intact PV; in the pooled urine samples, PV constituted 29 and 69% of the radioactivity after the po and iv doses, respectively. The delta 4.5-3 alpha-hydroxy isomer of PV constituted 10% (po) and 2% (iv), and 6-epi-PV constituted 3% (po) and 1% (iv) of the urinary radioactivity. Negligible amounts of the lactones of PV or its isomers were detected in urine, plasma, or feces. At least 15 other metabolites were also present; none of these accounted for more than 6% of the total urinary radioactivity. For metabolite isolation, an aliquot of pooled urine samples, obtained after administration of the radioactive dose, was added as a tracer to urine samples obtained from healthy subjects after administration of single nonradiolabeled 40-mg oral doses of PV. Urinary metabolites were concentrated on an XAD-2 column, extracted with ethyl acetate, and purified by extensive preparative HPLC. In addition to isolation and identification of unchanged drug and the two isomeric metabolites described above, eight other metabolites were isolated and structural assignments were made based on HPLC, UV spectra, mass spectral analysis, and proton NMR.(ABSTRACT TRUNCATED AT 250 WORDS)