pitavastatin and Liver-Cirrhosis

Lipid lowering therapy with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors is increasingly used for the prevention of cardiovascular events, but they should be used with caution in patients with impaired liver function. We therefore studied the pharmacokinetics of pitavastatin in patients with liver cirrhosis.. Plasma concentrations of pitavastatin were determined after administration of 2 mg single-dose pitavastatin to 12 male patients with liver cirrhosis (six Child-Pugh grade A and six grade B). These results were compared with the single-dose pharmacokinetic results obtained from six male volunteers without liver disease.. Administration of 2 mg single-dose pitavastatin to patients with Child-Pugh grade A and grade B cirrhosis resulted in a 1.19- and 2.47-fold increase in Cmax and 1.27- and 3.64-fold increase in AUCt, respectively, when compared with normal subjects. The geomean Cmax of pitavastatin was 59.5 ng ml(-1), 70.7 ng ml(-1) and 147.1 ng ml(-1) in the control, Child-Pugh grade A and Child-Pugh grade B groups, respectively. The geomean AUCt of pitavastatin in the three groups was 121.2 ng h(-1) ml(-1), 154.2 ng h(-1) ml(-1) and 441.7 ng h(-1) ml(-1), respectively. The geomean Cmax of pitavastatin lactone was 20.3 ng ml(-1), 19.1 ng ml(-1) and 9.9 ng ml(-1) in the control, Child-Pugh grade A and grade B groups, respectively. The AUCt of pitavastatin lactone was 120.2 h(-1) ml(-1), 108.8 h(-1) ml(-1) and 87.5 h(-1) ml(-1), respectively.. The plasma concentration of pitavastatin is increased in patients with liver cirrhosis. In such patients, caution is required, although dose reduction may not be necessary in Child-Pugh A cirrhosis.

Topics: Adult; Area Under Curve; Enzyme Inhibitors; Humans; Liver Cirrhosis; Male; Middle Aged; Quinolines; Time Factors

It has been shown that a statin (3-hydroxy-3-methyl-glutaryl coenzyme reductase inhibitor) enhances a suppressive effect of angiotensin II type 1 receptor (AT1-R) blocker (ARB) on injury-induced transforming growth factor (TGF)-beta expression in kidneys. We have shown that TGF-beta plays a crucial role in the development of liver fibrosis. In this study, we tested whether a combinatory use of a statin (pitavastatin) and an ARB (candesartan) may further inhibit liver fibrogenesis in carbon tetrachloride (CCl4)-treated rats. Candesartan (8 mg/kg/day) significantly suppressed injury-induced TGF-beta 1 expression in livers, and attenuated fibrogenesis, as evaluated by masson-trichrome staining and hydroxyproline content in livers. Pitavastatin (2 mg/kg/day) alone did not affect liver fibrogenesis. However, it enhanced significantly the suppressive effects of candesartan on TGF-beta 1 expression and fibrogenesis. Although we do not know the underlying molecular mechanisms at this moment, these results suggest that a combinatory use of a statin and an ARB may confer beneficial effects on human liver fibrogenesis.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Carbon Tetrachloride; Depression, Chemical; Drug Synergism; Drug Therapy, Combination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Liver Cirrhosis; Male; Quinolines; Rats; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta