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Tissue selectivity of pravastatin sodium (pravastatin), lovastatin and simvastatin, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors was examined by measuring inhibition of de novo sterol synthesis and active drug concentrations in the liver, spleen and testis in rats after a single oral administration (25 mg/kg) of these drugs. Regarding tissue drug concentrations, all three drugs were liver selective: concentrations of drugs in the liver were about ten-times highcr than those in the spleen and testis. On the other hand, pravastatin was far more liver selective in inhibiting sterol synthesis than two other inhibitors: pravastatin inhibited de novo sterol synthesis in the liver but minimally in the spleen and testis, whereas lovastatin and simvastatin inhibited in all three tissues. Microautoradiographic and in vitro cellular-uptake studies demonstrated that pravastatin remained in the extracellular space in the spleen, whereas the other drugs entered the cell. We conclude that pravastatin exhibits a liver-selective inhibition of sterol synthesis because the agent permeates the cell membrane in the liver, but not in non-hepatic tissues.Pravastatin sodium (as pravastatin) [l -31, lovastatin [4] and simvastatin [5] are potent and specific inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a key enzyme of sterol synthesis [6]. It is desirable for these drugs to act selectively on the target organ, the liver, to allow normal cellular function in non-hepatic tissues and to minimize potential side effects.Conflicting results, however, have been reported with regard to tissue selectivity of HMG-CoA reductase inhibitors [3, 7, XI. Based on inhibition of sterol synthesis in cells in vitro [3, 71, in rat tissue slices [3] and in mice in vivo [7], we havc reported that pravastatin is more liver selective than lovastatin and simvastatin. These results have been supported by other investigators [9, lo]. On the other hand, based on the distribution of drugs in the liver relative to non-hepatic tissues, Germershausen et al. have concluded [8] that lovastatin and simvastatin are more liver selective than pravastatin.In the present study, this issue was addressed by examining the relationship between inhibition of de novo sterol synthesis and active drug concentrations of HMG-CoA reductase inhibitors in the same tissue samples of the liver, spleen and testis in rats after oral administration. In vitro cellular uptake and microautoradiographic studies using 14C-labelled drugs were performed to examine the cellular distribution of drugs in the liver and spleen.Correspondence to

Pravastatin sodium (Pravastatin, CS-514, SQ-31000, Mevalotin@) (FIG. 1) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme of cholesterol biosynthesis.In the present study, tissue selectivity of pravastatin in inhibition of cholesterol synthesis was investigated in vitro and in vivo, and its effect was compared with other HMG-CoA reductase inhibitors, such as lovastatin (MB-530B, Mevinolin, Mevacor@), simvastatin (MK-733, Synvinolin, Zocora) and ML-236B (Compactin, Mevastatin) (FIG. 1). Inhibition of cholesterol synthesis in vivo was measured by incorporation of radioactivity into sterol fraction 1 hr after intraperitoneal injection of [ I4C]acetate to mice which were orally administered these drugs 2 hr before the acetate injection. When pravastatin was administered to mice at the dose of 20 mglkg, cholesterol synthesis was inhibited about 90% in the liver and ileum, but the inhibition was less than 10% in the kidney, spleen, adrenal, testis, prostate and brain. This tissue selectivity of pravastatin was also demonstrated even in varying doses (5-40 mg/kg) and time (75-180 min) after drug administration. Other HMG-CoA reductase inhibitors, such as lovastatin and simvastatin in both the lactone and open acid forms, and ML-236B did not show such a tissueselective inhibition as pravastatin (FIG. 2).These results were further confirmed by the inhibition of sterol synthesis in various cultured cells and rat lenses (TABLE 1). In freshly isolated rat hepatocytes, pravastatin and other HMG-CoA reductase inhibitors similarly inhibited the sterol synthesis. In the cells from nonhepatic tissues and rat lenses, lovastatin, simvastatin and ML-236B exerted a similar inhibitory activity as observed in rat hepatocytes. In contrast, the inhibitory activity of pravastatin was much less potent in these nonhepatic cells and rat lenses. This tissue selectivity of pravastatin could be explained by lesser cellular uptake of pravastatin into nonhepatic cells.Thus, pravastatin is shown to be a more distinct tissue-selective inhibitor of sterol synthesis in vitro and in vivo than other HMG-CoA reductase inhibitors. REFERENCE 1. TSUJITA, Y. er al. 1986. Biochim. Biophys. Acta 877: 50-60.

Die Methylketone (I) reagieren nach Reformatskii zu den β‐Hydroxycarbonsäureestern (IIa), die zu den Carbonsäuren (IIb) verseift werden.