Journal of pharmacobio-dynamics最新文献

Relationship between structure and binding affinity to human serum albumin (HSA) has been studied for penicillin and cephem antibiotics. For penicillin analogs, a good correlation between the apparent affinity constants, Kapp, for HSA binding and the partition coefficient, Papp, determined in isobutyl alcohol-pH 7.4 phosphate buffer system was observed, indicating that the hydrophobic interaction of 6-substituent of penicillins with amino acid of HSA would play an important role for the binding. However, no correlation between the Kapp and Papp values was observed for cephem antibiotics. Mutual competitive displacement effects were demonstrated for the primary binding sites of cephalothin, cefazolin, cefotetan and cefatrizine, suggesting the presence of a common binding region in HSA among these cephem antibiotics examined. Significant differences were observed for the Kapp value among cephems having the same 3-substitute of N-methylthiotetrazole in the molecule, i.e., cefpiramide, cefotetan, cefoperazone, cefamandole, cefmenoxime, cefmetazole and cefbuperazone, suggesting that 7-substitute of cephem would play an important role for the binding with HSA. Moreover, comparing the binding affinity and the structure of 3-substitute for cephems, all of the analogs having a heterocycle bind strongly with HSA in spite of their low lipophilicity. These observations suggest that an interaction between heterocycle at the position 3 and HSA would contribute to an additional binding force for the binding of cephem antibiotics to HSA.

The inductive effects of pretreatment with 10 synthetic chloroflavone isomers and congeners (80 mg/kg/d for 3 d, i.p.) on hepatic microsomal monooxygenases were examined with male Wistar rats. All chloroflavone congeners, except 3'-chloroflavone (CF), significantly increased (1.2- to 2-fold) the content of total cytochrome P-450 (P-450s) in microsomes. The effects of these congeners were evaluated based on the activities of microsomal aminopyrine N-demethylase, aniline hydroxylase and scoparone (6,7-dimethoxycoumarin) O-demethylase, and the CO difference spectrum and sodium dodecyl sulfate-gel electrophoretogram of cytochrome P-450s. The results were compared with those of phenobarbital (PB), 3-methylcholanthrene (MC) and PB plus MC. Based mainly on effects on the CO difference spectrum and ratio of the two O-demethylase activities of scoparone, 2'-CF and 2',4'-dichloroflavone (DCF) were categorized as the PB-type, 4'-CF and 6,8-DCF as the MC-type, 3',6-DCF and 3',5',6-trichloroflavone as weak MC-type, and 6-CF and 2',6-DCF as mixed (PB plus MC)-type inducers. A comparison of chloroflavone isomers and congeners indicated that (1) the presence of the 2'-chloro substituent of the flavone system is a minimal requirement for exhibiting the PB-type effect, (2) the absence of the 2'-chloro substituent is possibly that for exhibiting the MC-type effect and (3) the induction potencies by individual chloroflavone congeners may not be related to the degrees of chlorination.

Effects of a new thyrotropin-releasing hormone (TRH) analog, N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]L-histidyl-L-prolinamide dihydrate (YM-14673), which improves experimentally induced memory dysfunction, on long-term potentiation (LTP) in the mossy fiber-CA3 system, were investigated using guinea pig hippocampal slices. At concentrations of 10(-7) M and 10(-6) M, YM-14673 significantly augmented LTP in a concentration dependent manner. The magnitude of effect of 10(-6) M YM-14673 was similar to that of 10(-6) M TRH. As LTP in the hippocampus is regarded as an elementary process of memory and learning, the augmenting effect of YM-14673 on LTP in the present study may contribute to this drug's ability to remedy memory dysfunction.

Platelets from stroke-prone spontaneously hypertensive rats (SHRSP) show severe hypofunctions accompanied by defective protein (P47) phosphorylation. To examine the mechanism of platelet hypofunctions, phospholipid metabolism in SHRSP was compared with that in Wistar Kyoto rats (WKY). Phosphatidylinositol (PI) content was 20% less in SHRSP than in WKY, but no changes were observed in other phospholipids. Incorporation of [3H]-arachidonic acid (AA) into PI and phosphatidylethanolamine (PE) was 12% and 11% lower, and that into phosphatidylcholine (PC) was 6% higher in SHRSP than in WKY. Thrombin-induced diacylglycerol and phosphatidic acid formation were similar in both groups of platelets. Thrombin-induced release of [14C]-AA from the labeled platelets and its metabolism to eicosanoids occurred at similar rates. These results suggest that reduced formation of diacylglycerol, an activator of protein kinase C (PKC), does not cause defective phosphorylation of P47, a substrate of PKC, in SHRSP. However it remains unclear how the lower PI content and the altered distribution of AA in PC and PE is related to SHRSP platelet hypofunctions.

To prove the free-ligand hypothesis for extravascular equilibration and tissue binding mechanism of beta-lactam antibiotics, the microdialysis technique has been employed for the lung, the muscle and the liver in rats. Cefminox, a cephem antibiotic, and SY5555, a new penem antibiotic, were used in the present study. During the constant infusion of each antibiotic with simultaneous infusion of antipyrine, the microdialysis studies were performed and the dialysate concentrations were determined. The dialysate concentration was extrapolated to the in vivo unbound concentration in tissue interstitial fluids (Cisf,u) according to the extrapolation method which was derived from the clearance concept. This extrapolation method incorporates the effective dialysis coefficient of a reference compound, antipyrine, which is used to correct the difference between in vivo and in vitro permeabilities of microdialysis fiber. The values of Cisf,u values for cefminox and SY5555 in the lung, muscle and liver were close to the unbound concentrations in the venous plasma leaving these organs. Furthermore, good coincidences were obtained between the unbound concentrations of SY5555 in lung and muscle interstitial fluids estimated from the total concentrations in homogenized tissues and those extrapolated by the microdialysis studies. Consequently, the present microdialysis studies provided the in vivo evidence that 1) the free-ligand hypothesis for extravascular equilibration of beta-lactam antibiotics is true, and that 2) beta-lactam antibiotics are restricted in the interstitial space in a noneliminating organ and bind only with albumin existing in this space.

The absorption and excretion of sodium prasterone sulfate (PS) (sodium dehydroepiandrosterone sulfate) were studied in rats after vaginal administration of 14C-PS. In late pregnant rats, maximum plasma level (Cmax) appeared at 2-4 h after dosing and both Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally with increased dose up to 4.0 mg/kg. The radioactivity administered was almost completely recovered from urine and feces during a 72 h postdosing period. The percentages of radioactivity excreted in urine and feces were 58% and 40% of the dose, respectively. The biliary excretion was 46% of the dose within 48 h and about half of the radioactive biliary excreta entered the enterohepatic circulation system. The vaginal absorption of PS was markedly affected by the estrous cycle stage and the progress of pregnancy. The vaginal absorption of PS was predominant at metestrus and diestrus and during late pregnancy.

The effect of insulin on glucose and 2-deoxyglucose uptake into isolated diaphragm was investigated in genetically diabetic KK-CAy mice, and in part in alloxan-treated mice. Concentration-response curves of insulin for glucose uptake (8.3 mM in vitro) for 1 h were shifted to the left in two kinds of diabetic model mice. Insulin-stimulated glucose uptake was biphasic; it was high 1 week, and returned to the normal level 4 weeks, after alloxan injection despite high blood glucose levels. Insulin-stimulated glucose uptake was the same at higher glucose levels (25 mM) as at 8.3 mM glucose for 1 h, despite an increase in basal glucose uptake (without insulin) in KK-CAy mice. Insulin-receptor kinase activity in diabetic KK-CAy mouse diaphragm also changed biphasically as the glucose concentration increased: an increase at 8.3 mM, but no increase at 16.7 mM or 25.0 mM glucose for 3 h-pretreatment including 1 h-insulin treatment. These results suggest that although the initial state of diabetes enhances insulin action, the prolonged hyperglycemia rather suppressed the insulin action in vivo.

The interaction of dicumarol and its seven other derivatives with human serum albumin (HSA), alpha 1-acid glycoprotein (AGP) and desialylatedAGP (asialoAGP) has been investigated by circular dichroism (CD) and fluorescence. The binding parameters of dicumarol and its derivatives obtained from fluorescence almost agreed with those obtained from CD. The binding data indicated that the total binding affinities (nK) to HSA were higher than the binding affinities to AGP and asialoAGP. Hydrophobic interaction was the driving force for the binding to all the three proteins and nK values in the binding process were found to be increased with the increase of hydrophobicity of the compound. This was evidenced by the attempts taken to correlate binding affinities with partition coefficients. Both electrostatic and van der Waals interactions were not found to play any significant role in the binding of these compounds to any of these three proteins. However, in case of the AGP and asialoAGP binding, apart from the hydrophobic interaction, some other forces may be involved as evidenced from the experimental data. Binding was exothermic, entropy driven and spontaneous. The change of enthalpy (delta H degree) was compensated for by the change in entropy (delta S degree). Relative contribution of hydrophobic interactions in the binding of these compounds to HSA was higher than to AGP or asialoAGP. Sialic acid was not found to impart any significant role in the binding of these compounds to AGP.

The nasal administration of digoxin was studied in rats and compared to intravenous, intraduodenal and rectal administration of the drug. The results indicated that the plasma level of digoxin after nasal administration was comparable to the level after intravenous injection. Administration by the intraduodenal and rectal routes resulted in considerably lower plasma levels. These data reveal that digoxin absorption across the nasal membranes is a reasonable approach. In the in situ nasal and intestinal perfusion experiments, digoxin disappeared from the perfusate following the apparent first-order kinetics. The nasal and intestinal absorption rate of digoxin was reduced by an increase in the perfusion volume. The plot of absorption rate constant against 1/volume resulted in a straight line, suggesting that digoxin is absorbed from nasal mucosa by a passive diffusion process.