Reference

Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Minsker, D. H.; MacDonald, J. S.; Robertson, R. T.; Bokelman, D. L. (Merck Sharp and Dohme Res. Lab., West Point, PA 19486, USA). Teratology, 28(3), 449-56 (English) 1983. CODEN: TJADAB. ISSN: 0040-3709. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) Oral administration of 800 mg/kg/day of mevinolin [75330-75-5] to rats from days 6-17 of gestation produced fetal malformations of the vertebrae and ribs in 29% of the litters, and there was a treatment-related increase in the incidence of gastroschisis. Mevinolinic acid (I) at 60 and 90 mg/kg/day also produced fetal malformations of the vertebrae and ribs, and these teratogenic manifestations were markedly suppressed by coadministration of the product of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, mevalonic acid, at 500 mg/kg. A diet supplemented with 0.5 or 1.0% cholesterol had no effect on the teratogenicity of I. Teratol. studies in rats with a dihydroxyheptanoic acid deriv. of mevinolin (II) [88929-29-7], a compd. 1/700 as potent as I as an inhibitor of HMG-CoA reductase, and dihydromevinolinic acid [77517-30-7], an inhibitor of this enzyme comparable in activity to I, indicated that the teratogenicity of these compds. was related to their relative enzyme inhibitory activity. II was not teratogenic at 150 mg/kg; in contrast, when dihydromevinolinic acid was administered at 50 and 100 mg/kg/day, its potency as a teratogenic agent was comparable to I. Thus, inhibitors of HMG-CoA reductase produced terata in rats and the teratogenic effects could be antagonized by coadministration of the enzyme product, mevalonic acid.

Determination of mevinolin and mevinolinic acid in plasma and bile by reversed-phase high-performance liquid chromatography

Determination of mevinolin and mevinolinic acid in plasma and bile by reversed-phase high-performance liquid chromatography. Stubbs, R. J.; Schwartz, M.; Bayne, W. F. (Merck Sharp and Dohme Res. Lab., West Point, PA 19486, USA). J. Chromatogr., 383(2), 438-43 (English) 1986. CODEN: JOCRAM. ISSN: 0021-9673. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) A reversed-phase HPLC method with UV detection was developed for detn. of mevinolin [75330-75-5] and mevinolinic acid [75225-51-3] in plasma and bile samples from rats and dogs receiving doses of mevinolin and mevinolinic acid, resp., as well as in human plasma after an oral dose of mevinolinic acid. Plasma samples were prepd. for anal. by using a bonded phase extn. cartridge followed by isocratic HPLC elution using ammonium phosphate buffer and acetonilrile. Bile samples were injected directly and gradient HPLC Lution with the same solvents was used. Both mevinolin and mevinolinic acid were detected at 236 nm after sepn. on a C18 Sepralyte column. Me mevinolinic acid was used as an internal std. The limits of detection for both compds. in plasma was 25 ng/mL. The std. curve was linear between 25-1000 ng/mL for both compds. and all points had a relative std. deviation of 7.8% or less. The abs. recoveries of mevinolinic acid and the internal std. were around 95%. The recovery of mevinolin was around 85%.