Studies on the metabolic inversion of the 6'chiral center of simvastatin.
In two simvastatin (SV) metabolites the 6' alpha-methyl of SV is oxidized to either 6' beta-CH2OH (I) or 6' beta-COOH (II). A possible intermediate is 6' exomethylene SV (III). When Sprague Dawley rats received an i.v. dose of [14C] III (1 mg/kg) metabolite II was excreted in bile. When dogs received an i.v. dose of [14C] III together with either [3H] SV (1 mg/kg) or its hydroxy acid form, [( 3H] SVA) (10 mg/kg), both 3H and 14C I and II were excreted in bile. These results strongly indicate that I and II are secondary metabolites of SV formed from III perhaps via a common aldehyde intermediate.
Vickers
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Merck Sharp & Dohme Research Laboratories West Point, Pennsylvania 19486.
Duncan
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CA
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006868:Hydrolysis; D007536:Isomerism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D011865:Radioisotope Dilution Technique; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin; D014316:Tritium
D000924:Anticholesteremic Agents; D002250:Carbon Radioisotopes; D014316:Tritium; D008148:Lovastatin; D019821:Simvastatin