To gain a better understanding of the metabolic properties between the open acid and lactone form of HMG-CoA reductase inhibitors (statins), the paper focused primarily on characterizing the metabolic properties of statins. We compared the metabolism of the acid and lactone forms of several statins, including atrovastatin, simvastatin, cerivastatin fluvastatin, pitavastatin and rosuvastatin with respect to metabolic clearance, CYP enzymes involved and drug-drug interactions. A remarkable increase in metabolic clearance was noted for all lactones compared with all acids except for pitavastatin lactone. The metabolic clearances of the atrovastatin, simvastatin, cerivastatin, fluvastatin and rosuvastatin lactones were 73-, 70-, 30-, 7- and 64-fold higher, respectively, than those of the corresponding acids. CYP2Cs were critically involved in the metabolism of cerivastatin, fluvastatin and pitavastatin acids. In contrast, CYP2Cs were not involved in the metabolism of the corresponding lactones and CYP3A4 was mainly involved. Moreover, a substantial difference in the metabolic inhibition of statins was found between acids and lactones. Overall, the study demonstrates that CYP-mediated metabolism of lactones is also a common metabolic pathway for statins and that the CYP3A4-mediated metabolism of the lactone forms clearly will need to be taken into account in assessing mechanistic aspects of drug-drug interaction involving statins.

NK-104 is a synthetic inhibitor of 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with very potent lipid-lowering effect. Absorption, distribution, metabolism and excretion of NK-104 were investigated after a single oral or intravenous administration of 14C-NK-104 at a dose of 1 mg/kg to rats, mainly males.1. The total radioactivity in plasma reached maximum levels within 1 hr after oral administration to male and female rats, and was followed by the elimination process consinting of three exponential. The T1/2 in the terminal phase was relatively long (12 ?? 18 hr). Although the Cmax was 325 and 415 ng eq./ml in males and females, respectively, the AUC was similar indicating no sex-related difference. 2. The tissue distribution was examined by both whole body autoradiography and quantitative radioas say. Following oral administration to rats, the radioactivity was selectively distributed to the liver, a target organ of this drug. The Cmax was approximately 54 times higher in the liver than in plasma. 3. Almost all the radioactivity was excreted into feces after oral or intravenous administration to male and female rats, respectively. Biliary excretion was 75% up to 48 hr after oral administration and most of the drug was subjected to entero-hepatic circulation. 4. After oral administration to rats, the unchanged NK-104 was detected as the main component and a small amount of several metabolites was also detected in plasma and various tissues. In particular, the Cmax and AUC of NK-104 in the liver were approximately 20 and 30 times, respectively, higher than those in plas ma. In the present study, it is concluded that NK-104 is hardly metabolized via P-450 mediated oxidation resulting in the formation of few products of ƒÀ-oxidation.

No abstract

[2][3][4]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide hydrochloride (K-604, 2) has been identified as an aqueous-soluble potent inhibitor of human acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also known as SOAT)-1 that exhibits 229-fold selectivity for human ACAT-1 over human ACAT-2. In our molecular design, the insertion of a piperazine unit in place of a 6methylene chain in the linker between the head (pyridylacetamide) and tail (benzimidazole) moieties led to a marked enhancement of the aqueous solubility (up to 19 mg/mL at pH 1.2) and a significant improvement of the oral absorption (the C max of 2 was 1100-fold higher than that of 1 in fasted dogs) compared with those of the previously selected compound, 1. After ensuring the pharmacological effects and safety, we designated 2 as a clinical candidate, named K-604. Considering the therapeutic results of ACAT inhibitors in past clinical trials, we believe that K-604 will be useful for the treatment of incurable diseases involving ACAT-1 overexpression.

An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer’s disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood–brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.