Abstract
Pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, exhibits liver-selectivity in inhibiting sterol synthesis, when administered as a single oral dose to mice or rats, whereas lovastatin and simvastatin do not. This may be due to the fact that pravastatin is distributed intracellularly, to a large extent, in the liver and extracellularly in nonhepatic tissues. In the present study, we examined whether the difference in liver-selectivity among these three HMG-CoA reductase inhibitors observed in single-dose studies was preserved after repeated oral administrations of drugs to mice.De novo sterol synthesis in different tissues of mice was examinedin vivo three hours after the last dose of drug by measuring incorporation of intraperitoneally injected [14C]acetate into total sterols. Pravastatin administered orally for 11 consecutive days at 5 and 10 mg/kg exhibited a greater liver-selectivity than lovastatin and simvastatin: sterol synthesis was inhibited more than 60% in the liver by all three drugs, whereas that in nonhepatic tissues was inhibited less than 10% by pravastatin and more than 30% by lovastatin and simvastatinin in most of the nonhepatic tissues examined. Pravastatin administered orallyfor 11 consecutive days at 10 mg/kg caused more selective inhibition of sterol synthesis in liverex vivo than two other inhibitors at the same dose. Pravastatin inhibitedde novo sterol synthesis from [14C]acetate into sterol fraction in the liver slicesin vitro, but minimally in those of the spleen and testis, whereas lovastatin and simvastatin inhibited in those of all three tissues. Since the drug concentrations determined in the same tissue samples of the liver, spleen, and testis were almost comparable among the three drugs, it was suggested that the cellular distribution profiles of pravastatin observed in a single-dose study were preserved in the multiple-dose study. We conclude that the difference in tissue-selectivity between pravastatin and the other two inhibitors to inhibit sterol synthesis in mice is maintained, regardless of the duration of administration.
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Abbreviations
- HMG-CoA:
-
3-hydroxy-3-methylglutaryl CoA
References
Serizawa, N., Nakagawa, K., Hamano, K., Tsujita, Y., Terahara, A., and Kuwano, H. (1983) Microbial Hydroxylation of Ml-236B (compactin) and Monacolin K (MB-530B),J. Antibiot. 36, 604–607.
Serizawa, N., Serizawa, S., Nakagawa, K., Furuya, K., Okazaki, T., and Terahara, A. (1983) Microbial Hydroxylation of ML-236B (compactin). Studies on Microorganisms Capable of 3β-Hydroxylation of ML-236B,J. Antibiot. 36, 887–891.
Tsujita, Y., Kuroda, M., Shimada, Y., Tanzawa, K., Arai, M., Kaneko, I., Tanaka, M., Masuda, H., Tarumi, C., Watanabe, Y., and Fujii, S. (1986) CS-514, a Competitive Inhibitor of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase-Tissue Selective Inhibitor of Sterol Synthesis and Hypolipidemic Effect on Various Animal Species,Biochim. Biophys. Acta 877, 50–60.
Rodwell, V.W., Norstrom, J.L., and Mitshelen, J.J. (1976) Regulation of HMG-CoA Reductase,Adv. Lipid Res. 14, 1–74.
Koga, T., Shimada, Y., Kuroda, M., Tsujita, Y., Hasegawa, K., and Yamazaki, M. (1990) Tissue-Selective Inhibition of Cholesterol Synthesisin vivo by Pravastatin Sodium, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor,Biochim. Biophys. Acta 1045, 115–120.
Koga, T., Fukuda, K., Shimada, Y., Fukami, M., Koike, H., and Tsujita, Y. (1992) Tissue Selectivity of Pravastatin Sodium, Lovastatin and Simvastatin,Eur. J. Biochem. 209, 315–319.
Komai, T., Shigehara, E., Tokui, T., Koga, T., Ishigami, M., Kuroiwa, C., and Horiuchi, S. (1992) Carrier-Mediated Uptake of Pravastatin by Rat Hepatocytes in Primary Culture,Biochem. Pharm. 43, 667–670.
Fujioka, T., Nara, F., Tsujita, Y., Fukushige, J., Fukami, M., and Kuroda, M. (1994) The Mechanism of Lack of Hypocholesterolemic Effects of Pravastatin Sodium, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, in Rats,Biochim. Biophys. Acta 1254, 7–12.
Reihner, E., Rudling, M., Stahlberg, D., Berglund, L., Ewerth, S., Bjorkhem, I., Einarsson, K., and Angelin, B. (1990) Influence of Pravastatin, a Specific Inhibitor of HMG-CoA Reductase, on Hepatic Metabolism of Cholesterol,N. Engl. J. Med. 323, 224–228.
Ma, P.T., Gil, G., Sudhof, T.T., Bilheimer, D.W., Goldstein, J.L., and Brown, M.S. (1986) Mevinolin, an Inhibitor of Cholesterol Synthesis, Induces mRNA for Low Density Lipoprotein Receptor in Livers of Hamsters and Rabbits,Proc. Natl. Acad. Sci. USA 83, 8370–8374.
Kume, N., Kita, T., Mikami, A., Yokode, M., Ishii, K., Nagano, Y., and Kawai, C. (1989) Induction of mRNA for Low-Density Lipoprotein Receptors in Heterozygous Watanabe Heritable Hyperlipidemic Rabbits Treated with CS-514 (Pravastatin) and Cholestyramine,Circulation 79, 1084–1090.
Germershausen, J.I., Hunt, V.M., Bostedor, R.G., Bailey, P.J., Karkas, J.D., and Alberts, A.W. (1989) Tissue Selectivity of the Cholesterol-lowering Agents Lovastatin, Simvastatin and Pravastatin in Ratsin vivo, Biochem. Biophys. Res. Commun. 158, 667–675.
Mosley, S.T., Kalinowski, S.S., Schafer, B.L., and Tanaka, R.D. (1989) Tissue-Selective Acute Effects of Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase on Cholesterol Biosynthesis in Lens,J. Lipid Res. 30, 1411–1420.
Tobert, J.A. (1988) Efficacy and Long-Term Adverse Effect Pattern of Lovastatin,Am. J. Cardiol. 62, 128J-134J.
Norman, D.J., Illingworth, D.R., Munson, J., and Hosenpud, J. (1988) Myolysis and Acute Renal Failure in a Heart-Transplantation Recipient Receiving Lovastatin,N. Engl. J. Med. 318, 46–47.
East, C., Alivizatos, P.A., Grundy, S.M., Jones, P.H., and Farmer, J.A. (1988) Rhabdomyolysis in Patients Receiving Lovastatin after Cardiac Transplantation,N. Engl. J. Med. 318, 47–48.
Tobert, J.A., Shear, C.L., Chremus, A.N., and Mantell, G.E., (1990) Clinical Experience with Lovastatin,Am. J. Cardiol. 65, 23F-26F.
Barth, J.D., Kruisbrink, O.A., and Van Dijk, A.L. (1990) Inhibitors of Hydroxyglutaryl Coenzyme A Reductase for Treating Hypercholesterolemia,Br. Med. J. 301, 669.
Vgontzas, A.N., Kales, A., Bixler, E.O., Manfredi, R.L., and Tyson, K.L. (1991) Effects of Lovastatin and Simvastatin on Sleep Efficiency and Sleep Stages,Clin. Pharmacol. Ther. 50, 730–737.
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Koga, T., Kikuchi, T., Miyazaki, A. et al. Tissue-selective inhibition of sterol synthesis in mice by pravastatin sodium after a single or repeated oral administrations. Lipids 30, 775–779 (1995). https://doi.org/10.1007/BF02537806
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DOI: https://doi.org/10.1007/BF02537806