Young Sun Lee

Effect of coix on plasma, liver, and fecal lipid components in the rat fed on lard- or soybean oil-cholesterol diet.

To determine the influence of dietary coix on lipid metabolism, the effect of coix on plasma, liver, and fecal lipid components was studied using Sprague-Dawley male rats. All rats were divided into four groups, and the rats of each group were fed the coix-lard diet, coix-soybean oil diet, or the respective control diets (containing 1% cholesterol each) for 27 days. Plasma and liver cholesterol levels in the coix-lard diet group significantly decreased as compared with those in the control group, whereas there was no effect on the fecal excretion of cholesterol. The decreases in the concentrated liver triglyceride and the increases in the fecal excretion of triglyceride were found in coix-soybean oil diet group. Moreover, liver and fecal phospholipid levels in both coix diet groups significantly increased. But there were no significant changes in plasma and fecal bile acids in either coix diet group. These results suggest the possibilities that coix may have an inhibitory action on cholesterol synthesis in liver, a facilitating effect on biliary excretion of triglyceride, and an acceleratory action on phospholipid synthesis in liver.

Dose-dependent pharmacokinetics and first-pass effects of mirodenafil, a new erectogenic, in rats.

The pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous (5, 10, 20 and 50u2009mg/kg) and oral (10, 20 and 50u2009mg/kg) administration of mirodenafil, and the first‐pass effect of mirodenafil after intravenous, oral, intraportal, intragastric and intraduodenal (20u2009mg/kg) administration of mirodenafil were evaluated in rats. The pharmacokinetics of mirodenafil and SK3541 were dose‐dependent after both intravenous and oral administration of mirodenafil due to the saturable hepatic metabolism of mirodenafil. After oral administration of mirodenafil, approximately 2.59% of the oral dose was not absorbed, the F value was approximately 29.4%, and the hepatic and gastrointestinal first‐pass effects of mirodenafil were approximately 21.4% and 54.3% of the oral dose, respectively. The low F value of mirodenafil in rats was mainly due to considerable hepatic and gastrointestinal first‐pass effects in rats. The equilibrium plasma‐to‐blood cell partition ratios of mirodenafil were independent of the initial blood mirodenafil concentrations of 1–10u2009µg/ml; the mean values were 1.08–1.21. The plasma binding values of mirodenafil to rat plasma was 87.8%. Copyright

Gas Chromatographic Analysis of Methiocarb and its Metabolites in Soil and Rice

SummaryA new method to determine the amount of methiocarb and its two metabolites, the sulfoxide and sulfone in soil and rice plant is described. The method consists of extraction of samples with acetone, filtration, separation of methiocarb and its metabolites through a Florisil column, and gas chromatographic determination. Since the degradation of methiocarb to 3,5-dimethyl-4-methylthiophenol (DMMP) is commonly observed during GC analysis, methiocarb was converted to DMMP via chemical hydrolysis after column chromatography. Reasonable recoveries for routine analysis were obtained and the limit of quantitation (LOQ) with GC/FPD were 0.5, 2 and 2 ng for DMMP sulfoxide and sulfone, with a signal to noise ratio of 4. In all rice samples, no detectable residues were found, however DMMP and methiocarb sulfoxide were found in some straw samples. In field soil samples, no sulfone was detected in all samples and methiocarb showed typical degradation curves with a half life of 8 days after treatment. A five-fold longer half life was observed in indoor studies.

Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541

PURPOSEnThis study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite, SK3541, using various hepatic CYP inducers and inhibitors in rats.nnnMETHODSnMirodenafil at a dose of 20 mg/kg was administered intravenously to control rats and rats pretreated with various CYP inducers and inhibitors. The disappearance of SK3541 was also measured in vitro hepatic microsomes of rats with and without CYP inducer and inhibitors.nnnRESULTSnCompared to controls, in rats pretreated with 3-methylcholanthrene, orphenadrine, and dexamethasone (main inducers of CYP1A1/2, 2B1/2, and 3A1/2, respectively), the non-renal clearances (CLNRs) of mirodenafil were significantly faster (by 39.4%, 59.3%, and 63.9%, respectively). However, compared to controls, in rats pretreated with quinine and troleandomycin (main inhibitors of CYP2D subfamily and 3A1/2, respectively), the CLNRs of mirodenafil were significantly slower (by 36.1% and 33.2%, respectively). In rat hepatic microsomes spiked with furafylline, quinine, and troleandomycin (main inhibitors of CYP1A2, 2D subfamily, and 3A1/2, respectively), the intrinsic clearances (CLints) for the disappearance of SK3541 were significantly slower (by 18.4%, 35.3%, and 51.5%, respectively) than controls. Also in rat hepatic microsomes pretreated with orphenadrine (a main inducer of CYP2B1/2), the CLint for the disappearance of SK3541 was significantly faster (by 55.5%) than controls.nnnCONCLUSIONSnThe above data suggest that hepatic CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 are involved in the metabolism of both mirodenafil and SK3541 in rats.

Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate: contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2

Objectives It has been reported that mirodenafil is primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2, 2B1/2, 2D1 and 3A1/2 in rats. It has also been reported that the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 increases and that of hepatic CYP2D1 decreases in rats with acute renal failure induced by uranyl nitrate (U‐ARF rats). Thus, the pharmacokinetics of mirodenafil were studied in control and U‐ARF rats.

Pharmacokinetics of mirodenafil and Its two metabolites, SK3541 and SK3544, in spontaneously or DOCA–salt-induced hypertensive rats

Hypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20u2009mg/kg) to 6‐week‐old rats (with blood pressure within the normotensive range) and 16‐week‐old spontaneously hypertensive rats (SHRs) and their age‐matched control normotensive Kyoto–Wistar (KW) rats, and 16‐week‐old deoxycorticosterone acetate–salt‐induced hypertensive rats (DOCA–salt rats) and their age‐matched control Sprague–Dawley (SD) rats were compared. It was found that time‐averaged renal clearance (Clr) was of minor importance and that time‐averaged non‐renal clearance (Clnr) was dominant. In both 6‐ and 16‐week‐old SHRs, the Clnrs and areas under the curve (AUCs) of intravenous mirodenafil were significantly smaller and greater than those of the controls, but in 16‐week‐old DOCA–salt rats, they were comparable to the controls. Although the AUC of oral mirodenafil in 16‐week‐old SHRs was comparable to the controls, the Clnrs (or total body clearances, Cls) of intravenous mirodenafil and intestinal intrinsic clearances were significantly smaller than the controls and comparable to the controls for both 6‐ and 16‐week‐old SHRs, unlike in the 16‐week‐old DOCA–salt rats. The above data suggest that the significantly smaller Clnr and greater AUC of intravenous mirodenafil and comparable AUC of oral mirodenafil in 16‐week‐old SHR could be due to the hereditary characteristics of SHRs, and not due to the hypertensive state itself. Copyright

Gender differences in pharmacokinetics and pharmacodynamics of azosemide in rats

Gender differences in pharmacokinetics and pharmacodynamics of azosemide were evaluated after intravenous, 10 mg kg(-1), and oral, 10 mg kg(-1), administration to male and female rats. After intravenous administration to male rats, the percentages of intravenous dose of azosemide recovered from entire gastrointestinal tract at 24 h (13.2 versus 3.93%) was significantly greater than those in female rats. In male rats, the nonrenal clearance of azosemide tended (p<0.066) to be faster and kidney weight tended (p<0.068) to be greater than those in female rats. After oral administration of azosemide to male rats, the 8-h urinary excretion of potassium (0.395 versus 0.766 mmol g(-1) kidney) and 8-h kaluretic efficiency (55.9 versus 284 mmol mg(-1)) decreased significantly compared with female rats.