Journal of pharmacobio-dynamics最新文献

Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4 +/- 2.2 (mean +/- S.E.) to 10.2 +/- 5.1 h (p < 0.05) and the total body clearance was increased from 24.6 +/- 3.1 to 45.1 +/- 5.1 ml/h/kg (p < 0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (> or = 0.1 mumol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 mumol/l; PEMA 1.7 mumol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 mumol/l; PEMA 11.0 mumol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT.(ABSTRACT TRUNCATED AT 250 WORDS)

A new compound, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101) was synthesized, and its skin penetration enhancing activity was examined by using 14C-indomethacin as a penetrant. A solution of HPE-101 and indomethacin was applied to a cloth pad affixed onto an adhesive tape to give a HPE-101 patch, and the patch was applied to hairless mouse skin. The amount of percutaneously absorbed indomethacin was determined by measuring the radioactivity excreted in urine for 24 h after application. 1) Azone and decylmethyl sulfoxide, enhanced markedly the percutaneous absorption of indomethacin when the propylene glycol-ethanol (9:1 v/v) mixture was used as the solvent. 2) Among various penetration enhancers dissolved in the indomethacin solutions and applied to screen for penetration enhancing activity, HPE-101 was found to be the most prominent. 3) Solvents containing more than 3% (w/w) of HPE-101 produced a plateau level of the penetration enhancing activity. 4) Daily application of 1% (w/w) solutions of HPE-101 or Azone increased the daily excretion of indomethacin significantly above the level excreted on the previous day. However, repeated daily application beyond 3 d gave a steady state excretion of indomethacin. 5) The mouse skin was pretreated with 3% (w/w) solutions of HPE-101 or Azone for 24 h on the 1st day, and the indomethacin solution was applied for 24 h on the 3rd day and 7th day to examine the recovery of skin barrier function. Enhanced excretion of indomethacin was still noted on the 3rd day, but enhancement was not observed on the 7th day.

The distribution of zonisamide, a new antiepileptic drug, in erythrocytes and in brain was studied to clarify the factors influencing its distribution in epileptic patients. In both humans and rats, zonisamide was concentrated significantly in erythrocytes in a saturable manner. When the effective concentration of zonisamide in serum was compared with that in blood in nine refractory epileptic patients taking zonisamide chronically, the variation in effective serum concentration was significantly larger than that in blood concentration. In rats, the distribution in the brain also showed saturability. These results suggest that differences in saturable binding to various tissues may contribute to the wide variation that occurs in the effective serum concentration of zonisamide in epileptic patients and that monitoring of the blood concentration of zonisamide may provide useful information for treatment with this drug.

MH61 is an acrosome-reacted sperm-specific monoclonal antibody. The antibody-coated beads effectively analyze the acrosomal status of human sperm. However, the nature of the antigen was not known. The antigen was purified by immunoprecipitation and SDS-PAGE followed by blotting on PVDF paper. The N-terminal sequence of the antigen was analyzed by an automated protein sequencer. An exactly matching sequence was found in CD46, that is also known as a membrane cofactor protein.

This study was performed to investigate the influence of the dosing route on chronopharmacological aspect of valproic acid (VPA) in mice, comparing the oral and rectal route. ICR male mice, housed under a standardized light-dark cycle (lights on from 0700 to 1900), were orally or rectally administered 400 mg/kg VPA each at the following scheduled time: 0900, 1300, 1700, 2100, 0100 and 0500. VPA concentrations in plasma and brain were determined by gas-liquid chromatography. There was a circadian rhythm in the electroshock seizure (ES) threshold 30 min after oral VPA administration, with the highest value at the midlight (1300) and the lowest at the middark (0100) (p < 0.01). A significant circadian rhythm was also found in plasma and brain VPA concentrations 30 min after oral administration (p < 0.01). This finding is related to the rhythm in the ES threshold. In contrast to oral administration, no circadian rhythm in the ES threshold, plasma and brain VPA concentrations was observed after rectal administration. These values after rectal dosing showed higher levels in comparison to those after oral dosing. Thus, the rectal route for VPA might have merit to eliminate the time-dependent changes in VPA pharmacologic action and kinetics. The timing of drug administration is an important factor that must be carefully controlled in drug pharmacokinetic and pharmacodynamic studies and must be considered in planning dosing routes.

Following in vivo treatment with carrageenan, sex-related differences in alteration of hepatic drug metabolism were found in the rat. In adult male rats, marked decreases were observed in hepatic 9000 x g supernatant cytochrome P-450 content and in the biotransformation of hexobarbital, aminopyrine, ethylmorphine, and meperidine. Hexobarbital hypnosis was significantly prolonged by carrageenan treatment in intact and testectomized animals as compared to their respective controls. Although carrageenan-treated intact animals slept 480% longer, carrageenan-treated testectomized rats slept only 60% longer than the respective control animals. However, testectomy or administration of 17 beta-estradiol to testectomized male rats did not inhibit the monooxygenase activities by carrageenan-treatment. Furthermore, administration of testosterone to ovariectomized female rats did not antagonize the inhibitory effects of the carrageenan-induced inflammation. The inhibitory effects produced by carrageenan-induced inflammation on the microsomal enzyme system were observed only in mature male rats and were not observed in mature female rats or in sexually immature rats of either sex. Thus, these results suggest that the inhibitory effects of carrageenan-induced inflammation on hepatic 9000 x g supernatant monooxygenases in the male rat are partially mediated through the toxic action of carrageenan-induced inflammation on androgen-dependent factors in this enzyme system.

The effect of selenium administered acutely or chronically on the hepatic microsomal drug-metabolizing system has been investigated in mice. After 72 h following acute administration of selenium (7.5 mg/kg, i.p.), there was a significant inhibition of the activities of aminopyrine (AM) N-demethylase and ethylmorphine (EM) N-demethylase, and cytochrome P-450 levels but no change in the activities of aniline (AN) hydroxylase, 7-ethoxycoumarin (EC) O-deethylase, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and reduced nicotinamide adenine dinucleotide (NADH)-ferricyanide reductase, and cytochrome b5 content. Chronic administration of selenium in the drinking water (1 or 2 ppm selenium) for 12 weeks, resulted in no alteration in any of the parameters measured. However, significant decreases in activities of AM N-demethylase and AN hydroxylase, and cytochrome P-450 levels were detected in animals given higher doses of selenium (4 or 8 ppm selenium). Following the in vitro additions of selenium to hepatic microsomes obtained from untreated mice, selenium inhibited the AM N-demethylase, AN hydroxylase and 7-EC O-deethylase in a concentration-dependent manner, but no alteration in NADPH-cytochrome c reductase and cytochrome P-450 levels was observed. These results indicate that selenium is a specific from inhibitor of hepatic monooxygenase.

The inhibitory effects of 12 synthetic N6-alkyl cAMPs, 8-substituted cAMPs and cAMP alkylphosphoramidate derivatives (50 or 100 mg/kg, bolus, i.p.) on serum GOT and GPT activities and hepatocyte cytoplasmic vacuolation were examined in male Fischer 344 rats, which were exposed to CCl4 (0.5 mg/kg, p.o.) 30 min prior to the administration of cAMP derivatives. In CCl4-treated rats 6 h later, serum GOT and GPT levels were elevated 10- and 12-fold higher than those of vehicle rats, respectively. Treating CCl4-exposed rats with all cAMP derivatives, except those of alkylphosphoramidate, significantly decreased the levels of serum enzymes. Based on the effects of both serum GOT and GPT elevation, N6-butyl- and N6-heptyl-cAMP were the most potent. It was also observed histopathologically, that both compounds inhibited the occurrence of cytoplasmic vacuolation in CCl4-treated liver cells. This is the first report that cAMP derivatives possess a protective effect in the liver injury model induced by CCl4.

Ring A aromatization of testosterone sulfate (TS), using human term placental microsomes as a enzyme source, was examined under a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-generating system. The aromatization to estradiol 17-sulfate (ES) without removal of the C-17 conjugate group was confirmed. Judging from the results of various experiments, including an inhibition experiment, the conversion was considered to occur by placental aromatase. Apparent Km and Vmax values for this aromatization were determined to be 37.4 microM and 330 pmol/mg protein/min respectively. The physiological role of direct conversion of TS by placenta to ES is discussed in connection with pregnancy.

The effect of gastrin on secretin binding sites in the stomach was studied using the plasma membranes from rat gastric mucosa and vascularly perfused rat stomach. Tetragastrin transiently increased secretin binding to the mucosal plasma membranes. In the perfused stomach secretin binding was also modulated by the inclusion of tetragastrin or human [Leu15] gastrin I in the perfusate. However, histamine did not show such a modulatory effect. Tetragastrin had an insignificant effect on secretin binding sites in rat pancreas. These results suggest that the direct modulation of secretin binding by gastrin to its receptors may be involved in the inhibitory action of secretin on acid secretion induced by gastrin.