Influence of high-fat meal on the absorption of a silicon — containing amide,an inhibitor of acyl — coa: Cholesterol acyltransferase,in man

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-l-phenylethyl] propanamide (DMPP), an inhibitor of acyl-CoA: cholesterol acyltransferase, have been examined in 18 healthy male volunteers who received an oral dose of either ¹⁴C-DMPP or ³H-DMPP immediately following a high-fat meal, or ³H-DMPP in the fasting state. DMPP was poorly absorbed in the fasting subjects. Administration with a high-fat meal significantly increased the extent of absorption to 15 per cent of the dose. Simultaneous fitting of the blood levels and excretion data to a pharmacokinetic model showed that ca. 64 per cent of the absorbed DMPP was metabolized while the remainder was excreted intact via the bile. The routes of biotransformation included hydrolysis of the amide bond and oxidation of the phenyl ring. The apparent volumes of distribution for DMPP and its ¹⁴C and ³H labelled metabolites were 0.89,0.95, and 1.61kg^?1, respectively, suggesting that these materials were distributed into extravascular spaces. The metabolites of DMPP were partially excreted in urine, accounting for 1.2 per cent and 3.8 per cent of the postprandial ¹⁴C and ³H labelled doses, respectively. The elimination half-lives of DMPP and its ¹⁴C and ³H labelled metabolites were 2.8, 5.3, and 6.9 h, respectively.     

Disposition of fluvastatin, an inhibitor of HMG-COA reductase, in mouse, rat, dog, and monkey

The physiological disposition of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, has been studied in the mouse, rat, dog, and monkey using 14C- or 3H-labeled drug. Oral doses of fluvastatin were absorbed at a moderate to rapid rate. The extent of absorption was dose-independent and was essentially complete in all four species studied. However, the drug was subject to extensive presystemic hepatic extraction followed by direct excretion via the bile, thus minimizing the systemic burden and yielding high liver/peripheral tissue concentration gradients for fluvastatin and its metabolites. Only at high doses far exceeding the intended human daily dose of ca 0.6 mg kg-1 did fluvastatin bioavailability approach unity, apparently due to saturation of the first-pass effect. Dose-normalized blood levels of fluvastatin and total radioactivity were higher in the dog than in the other species, suggesting a smaller distribution volume in the former. Fluvastatin was partially metabolized before excretion, the extent of metabolism being smallest in the dog and greatest in the mouse. The half-life of intact fluvastatin ranged from 1-2h in the monkey to 4-7h in the dog. Regardless of the dose or dose route, the administered radioactivity was recovered predominantly in feces, with the renal route accounting for less than 8 per cent of the dose. No tissue retention of radioactivity was observed, and material balance was essentially achieved within 96h after dosing.     

Sex-dependent toxicity of a novel acyl-CoA:cholesterol acyltransferase inhibitor, YIC-C8-434, in relation to sex-specific forms of cytochrome P450 in rats.

YIC-C8-434 is a novel inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT). To clarify the toxicity of YIC-C8-434, the compound was given orally to Sprague-Dawley rats for 28 days at 0, 4, 20, 100, or 500 mg/kg/day. The toxicity of the drug differed significantly between male and female rats. In female rats treated at 500 mg/kg, many symptoms including moribund condition, suppression of weight gain and food consumption, abnormal blood chemistry, and decreases in organ weights (thymus, ovaries, and uterus) were observed. In male rats by contrast, no significant toxicity was observed at any dose. After a single administration of YIC-C8-434 at 500 mg/kg, female rats had a higher blood concentration of the compound than male rats. Little elimination of YIC-C8-434 was observed in female rats on analysis of drug-elimination kinetics. Furthermore, the metabolism of YIC-C8-434 was analyzed using rat hepatic microsomal preparations from both sexes. Consistent with the observations in vivo, hepatic microsomes from male rats better metabolized YIC-C8-434 than those from females. In addition, the metabolism of YIC-C8-434 by hepatic microsomes from male rats was blocked by SKF525A, a P450 inhibitor. Inhibition experiments using anti-rat CYP1A1, CYP1A2, CYP2B1, CYP2C11, CYP2E1, CYP3A2, and CYP4A1 antisera indicated that CYP3A2 played the predominant role in the metabolism of YIC-C8-434 in rats. Since there is less CYP3A2 in the liver of female than male rats, the involvement of CYP3A2 in YIC-C8-434 metabolism has implications for the sex-related metabolic activity and toxicity of YIC-C8-434.     

Update on the role of acyl-CoA:cholesterol acyltransferase inhibitors in atherosclerosis

Cardiovascular disease is one of the leading causes of mortality and morbidity in industrialised nations. Hypercholesterolaemia is one of a number of risk factors identified that influences the development and progression of atherosclerosis. While drugs such as HMGCoA reductase inhibitors or statins have been shown to significantly reduce cholesterol levels and the risk for cardiovascular disease, there is still a pressing need to identify other compounds that might further reduce the risk. One such class of drugs, currently in preclinical and clinical studies, is acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors. Two isoforms of ACAT have been identified; ACAT₁ has a more ubiquitous distribution in steroidogenic tissue, pancreas, intestine and macrophages and ACAT₂ is predominantly expressed in hepatocytes and intestines. In human tissues, ACAT₂ expression is high in foetal hepatocytes but declines in adult hepatocytes. Its expression remains unchanged in foetal and adult human intestines. ACAT enzymes participate in the assembly of chylomicrons and very low density lipoproteins (triglyceride rich lipoproteins) and also in the formation of cholesteryl ester storage droplets within cells residing in the vessel wall. The initial results from preclinical and clinical studies suggest that ACAT inhibitors may have a beneficial effect in altering lipid profiles and in retarding the progression of atherosclerotic disease.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and high-density lipoprotein-induced cholesterol efflux in macrophages

We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans.     

Pharmacological properties of R-755, a novel acyl-CoA:cholesterol acyltransferase inhibitor, in cholesterol-fed rats, hamsters and rabbits

R-755 (N-(2,6-diethylphenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f[l]benzothiophen-2-yl]urea), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, has been characterized in vitro, ex vivo and in vivo. R-755 potently inhibited ACAT activities, with IC50 values from 2.5 to 64 nM, in rabbit intestinal microsomes and several cell lines (CaCo-2, THP-1 and J774A.1 cells). R-755 reduced serum cholesterol and triglyceride levels and liver cholesterol contents in cholesterol-fed rats, hamsters and rabbits. Rabbits were fed a high cholesterol diet for 2 weeks and further fed the same diet containing R-755 for 2 weeks. R-755 dose-dependently reduced cholesterol content and ACAT activity in the aorta. When phorbol 12-myristate 13-acetate-treated THP-1 and J774A.1 cells were incubated in the medium containing 20% of serum from rats administered R-755, the ACAT activities of the cells were inhibited. Rabbits were fed a high cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without R-755 for 8 weeks. R-755 dose-dependently reduced the surface area with atherosclerotic involvement and cholesterol contents in the aorta, although plasma cholesterol level did not differ from that in the control group. These results suggest that R-755 is a potent hypolipidemic agent and has a direct antiatherosclerotic activity at the arterial wall.     

Effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase inhibitor,on serum cholesterol level and LDL cholesterol clearance in hamsters with induced hyperlipidemia

The effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on serum cholesterol levels was investigated in hyperlipidemic hamsters whose condition had been preestablished by diet. SMP-500 reduced the total serum cholesterol level in a dose-dependent manner. SMP-500 also reduced the hepatic free cholesterol content and markedly reduced the esterified cholesterol content compared with the control group. Interestingly, SMP-500 at a dose of 30 mg/kg increased LDL clearance in vivo. As SMP-500 at this dose potently lowered the total serum cholesterol level, the increased LDL clearance was identified as another mechanism for the cholesterol-lowering effect of SMP-500. However, unlike HMG CoA reductase inhibitors, SMP-500 did not affect cholesterol biosynthesis in HepG2 cells. Therefore the etiology of the increased LDL clearance is not yet clear, but the reduced hepatic free cholesterol may play an important role in this process. These results suggest that the cholesterol-lowering effect of SMP-500 is due, not only to the inhibition of ACAT, but also to the increase in cholesterol clearance from the blood. This finding supports the therapeutic potential of SMP-500 for the treatment of human hypercholesterolemia.     

Effects of NTE-122, an acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and lipid secretion from CaCo-2 cells, and cholesterol absorption in rats.

The effect of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol absorption was investigated. NTE-122 inhibited whole-cell ACAT activity in CaCo-2 cells, a human intestinal cell line, with an IC50 value of 4.7 nM. In CaCo-2 cells cultured on a membrane filter, NTE-122 pronouncedly inhibited the basolateral secretion of newly synthesized cholesteryl esters, and significantly reduced the basolateral secretion of newly synthesized triglycerides without influencing the cellular triglyceride synthesis. Furthermore, NTE-122 (1 mg/kg, p.o.) inhibited [14C]cholesterol absorption in rats. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing the absorption of dietary cholesterol.     

Acaterin, a novel inhibitor of acyl-CoA: cholesterol acyltransferase produced by Pseudomonas sp. A92.

Acaterin, a novel inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT), was isolated from a culture broth of Pseudomonas sp. A92 by Diaion HP-20 column chromatography, solvent extraction and reverse phase HPLC. Spectroscopic analyses of the compound yielded 3-(1-hydroxyoctyl)-5-methyl-2(5H)-furanone as the proposed structure. In the presence of oxidized low density lipoprotein, acaterin inhibited the synthesis of cholesteryl ester in macrophage J774 by 50% at a concentration of 45 microM. Acaterin also inhibited ACAT activity in the rat liver microsomes by 50% at a concentration of 120 microM. Kinetic studies suggested that inhibition of ACAT by acaterin was noncompetitive with respect to oleoyl-CoA.     

Discovery of novel acyl coenzyme a: cholesterol acyltransferase inhibitors: pharmacophore-based virtual screening, synthesis and pharmacology

The present study describes ligand‐based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r = 0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross‐validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds ( 47 and 48 ; predicted IC₅₀ = 1 nm ) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10 μg/mL) with IC₅₀ value of 3.6 and 2.5 nm , respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors.     

Pharmacokinetic properties of YM17E, an inhibitor of acyl coenzyme A: cholesterol acyl transferase, and serum cholesterol levels in healthy volunteers

  We conducted a single and repeat oral dose study of YM17E, a novel inhibitor of acyl coenzyme A (CoA): cholesterol acyltransferase, in healthy male volunteers to evaluate the pharmacokinetic profile, tolerability and effect of the drug on serum cholesterol. In the single administration study, YM17E was administered after a meal to two groups of subjects (each containing six subjects taking the drug and three taking placebo) receiving 3, 60 and 300 mg or 15, 60 and 450 mg YM17E, respectively. Plasma concentrations of unchanged drug following single oral administration at 3–300 mg after a meal increased with increasing dose. In contrast, plasma concentrations after administration of 450 mg were almost the same as after 300 mg. Unchanged YM17E was not detected in urine after single administration, suggesting that it was excreted via the bile or urine after metabolism. Five active metabolites (M1, M2-a, M2-b, M3 and M4) were observed in plasma at concentrations comparable to those of unchanged YM17E. Their plasma concentrations increased in a slightly greater than dose-dependent manner from 3 to 300 mg. The effect of food was studied in an open crossover design with a 1-week washout period. Twelve subjects received 150 mg YM17E in both the fasted and postprandial states. The AUC and C_max after fasting were closely similar to those after a meal, showing that bioavailability was not affected by food intake. In the repeated oral dose study, the subjects received test drug at 150 mg or 300 mg (n = 6 each) or placebo (n = 3) twice a day (after breakfast and after dinner) for 7 days. On days 1 and 7, the subjects received YM17E once a day (after breakfast) for evaluation of pharmacokinetic properties. After repeated oral administration of 150 mg b.d., plasma concentrations reached steady state by day 5 (mean C_min 48.6 ng · ml⁻¹). After repeated administration of 300 mg b.d., plasma concentrations prior to each daily morning dose increased up to the 5th day (mean C_min 166.6 ng · ml⁻¹) and then tended to decrease until the 7th day. No significant signs, symptoms or changes in serum cholesterol levels were observed during the single and repeated oral dose studies at 150 mg b.d. Although statistical analysis was not conducted because of the small number of subjects, all subjects receiving repeated oral administration of 300 mg twice daily showed a 25% decrease in serum cholesterol level on day 7, but also the simultaneous occurrence of diarrhoea. Received: 23 April 1996 / Accepted in revised form: 1 August 1996     

Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in the rabbit.

The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first-pass effect, its absolute bioavailability being 46 per cent. The steady-state volume of distribution of fluvastatin was 0.29 +/- 0.04 l kg-1 while the total body clearance was 0.33 +/- 0.05 1 h-1 kg-1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28 +/- 4 per cent of the oral dose and 32 +/- 3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg-1 day-1 beginning day 6 post-conception (p.c.), steady-state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25-50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0.92 and 0.97, respectively, on day 10 p.c. to 0.10 and 0.04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel decline, suggesting no tissue retention of the drug.     

Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and secretions of apolipoprotein B-containing lipoprotein and bile acids in HepG2

We studied the effect of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl) ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited [3H]oleate incorporation into cholesteryl esters in HepG2 cells incubated with 5 microg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect [3H]oleate incorporation into triglycerides and phospholipids and [14C]acetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from [14C]-cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver.     

Direct effect of an acyl-CoA:cholesterol acyltransferase inhibitor, F-1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice

The acyl-CoA:cholesterol acyltransferase (ACAT) enzyme is thought to be responsible for foam cell formation and the subsequent progression of atherosclerosis. The apolipoprotein E and low density lipoprotein receptor double knockout (apoE/LDLr-DKO) mouse is an animal model that develops severe hyperlipidaemia and atherosclerosis. Here we have examined the effect of oral administration of an ACAT inhibitor, F-1394, on atherosclerosis in apoE/LDLr-DKO mice fed a regular chow diet. In en face analysis, a dose of 10, 30, or 100 mg kg(-1) day(-1) F-1394 for 10 weeks reduced the extent of lesions visible in the aorta by 24, 28 and 38%, respectively, as detected by staining with oil red O, without affecting serum cholesterol level in these mice. At the highest dose 100 mg kg(-1) day(-1) of F-1394, the reduction was statistically significant. For quantitative analysis of the cellular and non-cellular components comprising the lesions at the aortic sinus, the effects of an oral dose of 100 mg kg(-1) day(-1) F-1394 for 15 weeks were studied. There was a significant reduction (31.9%) in the oil-red O-stained area in cross-sections of the aortic sinus. In addition, the neointimal area, as well as levels of ACAT-1 protein tended to be decreased (15.2 and 25.8%, respectively, not significant). However, the areas containing macrophages, smooth muscle cells, and collagen were not affected by F-1394. In vitro, F-1394 attenuated foam cell formation in mouse peritoneal macrophages. These results indicate that ACAT may be primarily responsible for lipid accumulation in atherosclerotic lesions, and that its inhibition diminishes the lipid deposition via a direct effect on macrophages in the arterial wall.     

Disposition of SK&F L-190144 in rats and monkeys after oral,intravenous or ocular administration

The objective of the study was to investigate the systemic disposition of ¹⁴C-SK&F L-190144 after single intravenous (10mg kg^?1) and oral (200 mg kg^?1) doses to rats and after single intravenous and ocular doses (0.33 mg kg^?1) to monkeys. After the intravenous dose, the blood concentration-time profile of ¹⁴C-SK&F L-190144 followed a rapid triexponential decline with half-lives of 2.5, 15, and 246 min in rats and 3, 19, and 2520 min in monkeys. The ¹⁴C-label in blood was mainly the parent compound. The terminal elimination half-life detected in rats using the urinary excretion rate-time data was 700 min. The total body clearance values were 17.6 ± 2.1 (mean ± SD, n = 6) and 1.11 ± 0.41 (n=4) mlmin^?1 kg^?1 for rats and monkeys, respectively. Both species had similar values of volume of distribution at the terminal phase, 4 to 6 l kg^?1, and similar excretion patterns, approximately 60 per cent and 30 per cent of the dose were excreted in the urine and feces, respectively. ¹⁴C-SK&F L-190144 was not absorbed orally in rats with the majority of the dose recovered in the feces. Following ocular administration to monkeys, the plasma drug concentrations peaked at 8 h post-dosing but did not reach a biexponential elimination phase until 18 h post-dosing, suggesting slow systemic absorption of drug from the ocular site. The monkeys excreted 42 per cent of the dose in urine and 50 per cent in feces after ocular administration. This increase in fecal excretion compared to the intravenous route of administration may have been due to the slow absorption by the ocular and nasal tissues altering the relative proportions of drug elimination via the renal and hepatic routes, or to a proportion of the dose passing into the gastrointestinal tract and exiting unabsorbed. Study results demonstrate similar excretion patterns and volume of distribution after intravenous administration in both species. The slow terminal elimination phase in monkeys was attributed to the low body clearance. The low oral bioavailability was possibly due to the poor partitioning behavior of the drug (logarithm of partition coefficient - 2.6). A significant fraction of the dose was absorbed in the body via the ocular route.     

Guineensine, an Acyl-CoA: cholesterol acyltransferase inhibitor, from the fruits of Piper longum

Bioactivity-guided fractionations for ACAT inhibitor led to the isolation of guineensine from the CHCl (3) extract of Piper longum. Its structure was identified by spectroscopic means (IR, UV, MS and NMR). Guineensine inhibited ACAT activity in a dose-dependent manner with an IC (50) value of 3.12 micro M.     

Preclinical safety evaluation of avasimibe in beagle dogs: an ACAT inhibitor with minimal adrenal effects.

Avasimibe, a novel inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), is currently being developed as an antiatherosclerotic agent. The preclinical safety and toxicokinetics of the compound were assessed in beagle dogs in an escalating-dose study and in repeated-dose studies of 2-, 13-, and 52-week duration. Oral (capsule) doses up to 1000 mg/kg b.i.d. were assessed in the escalating dose study and once-a-day doses up to 300 mg/kg, 1000 mg/kg, and 1000 mg/kg were assessed in the 2-, 13-, and 52-week studies, respectively. Avasimibe was found to be a substrate and inducer of hepatic CYP 3A, producing pronounced decreases in plasma drug concentrations subsequent to Day 1. Plasma drug concentrations plateaued markedly at doses above 100 mg/kg. Significant toxicologic findings were restricted to the higher doses (> or =300 mg/kg) and included emesis, fecal consistency changes, salivation, body weight loss, microscopic and clinical pathologic evidence of hepatic toxicity, and red blood cell (RBC) morphology changes. Mortality occurred at 1000 mg/kg due to hepatic toxicity. Toxicity was more closely associated with the exaggerated pharmacodynamic effects of the compound (e.g., marked serum cholesterol decreases) seen at the high doses of avasimibe used in these studies rather than with measures of systemic exposure (Cmax or AUC). Adrenal effects were noted only in the 52-week study and consisted of minimal to mild cortical cytoplasmic vacuolization and fibrosis at doses > or =300 mg/kg, with no change in adrenal weight. In conclusion, avasimibe is an ACAT inhibitor that has minimal adrenal effects in dogs, with dose-limiting toxicity defined by readily monitored and reversible changes in hepatic function.