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E Kokue

Publications and source records attributed to E Kokue.

At least 37 records · Page 2Linked to original sources
PubMed1996

Role of high-affinity folate-binding protein in the plasma distribution of tetrahydrofolate in pigs.

Stability and protein-binding properties of tetrahydrofolate (THF) in pig plasma were studied in vitro. THF in plasma was stable for more than 120 min when it existed in a bound form, whereas THF both in plasma ultrafiltrate and in plasma ultrafiltrate plus porcine albumin was degraded rapidly and disappeared soon after its addition. These results suggest that high-affinity folate-binding protein (HFBP) is related to the stability of THF. THF-protein binding kinetic analysis showed that porcine plasma had HFBP and low-affinity binding protein (albumin) for THF. Dissociation constant and maximal binding capacity of HFBP were calculated to be 0.4 and 70 nM, respectively, indicating that > 98% of endogenous plasma THF existed in bound form with HFBP. Porcine albumin was not essentially a protein that binds and protects endogenous THF from degradation. We conclude that most endogenous THF binds to HFBP and only the unbound form of THF is rapidly degraded in pig plasma. HFBP protects THF from degradation and allows THF to exist stably in pig plasma. In addition, HFBP may govern the species specificity of plasma folate distribution in pigs.

Animals↗
PubMed1996

Alteration of plasma folates in gestating sows and newborn piglets.

Plasma folates tetrahydrofolate (THF) and N5-methyltetrahydrofolate (5MF) were determined in nongestating, gestating, and lactating sows (2 to 4 yr old, 2-6 parities, n = 88) and in newborn, growing, and finishing pigs (0 to 158 days old, n = 191) with the use of high-performance liquid chromatography with an electrochemical detector. Plasma folates after folic acid injection (1 mg/kg iv) were also monitored in 2-day-, 2-wk-, and 2-mo-old pigs. In sows, plasma folates decreased significantly as pregnancy advanced. This was mainly due to the decrease of THF, which must be caused by the folate supply from the maternal body to the fetuses. In newborn piglets, levels of "total" plasma folates were much higher than those in adults (nongestating sows), and 5MF was the major folate content. This result may be related to the observation that, after folic acid injection, newborn piglets showed much higher metabolic activity of folic acid to 5MF than adults. Rapid and drastic decrease of plasma folate was observed during nursing in piglets, which is considered to be associated with the decrease of the metabolic activity of folic acid and rapid expansion of body volume together with negative folate intake during the nursing period.

Aging↗
PubMed1995

Enterohepatic circulation kinetics of bile-active folate derivatives and folate homeostasis in rats.

We examined the effect of enteric infusion of 5,10-methylenetetrahydrofolate (5,10-CH2-H4PteGlu), tetrahydrofolate (H4PteGlu), 10-formyltetrahydrofolate (10-HCO-H4PteGlu), and 5-methyltetrahydrofolate (5-CH3-H4PteGlu) on concentrations of plasma 5-CH3-H4PteGlu in rats. Concentrations of plasma 5-CH3-H4PteGlu rapidly decreased during continuous bile diversion, whereas initial levels of plasma 5-CH3-H4PteGlu were maintained by means of enteric infusion of 5-CH3-H4PteGlu at a dose of 3 nmol/h, which was approximately equal to total secretion of bile folates. Plasma 5-CH3-H4PteGlu levels were also maintained by the infusion of 5,10-CH2-H4PteGlu, H4PteGlu, or 10-HCO-H4PteGlu at the same dose as 5-CH3-H4PteGlu. The results indicate that folates secreted into the bile are reabsorbed through the intestine to regulate plasma concentrations of 5-CH3-H4PteGlu. We examined the secretion kinetics of bile folates after the intravenous injection of 5-CH3-H4PteGlu or folic acid (PteGlu) at 1 mg/kg body wt. When 5-CH3-H4PteGlu was injected, the bile secretion of folates other than 5-CH3-H4PteGlu increased by < 5 times the base level, whereas that of bile 5-CH3-H4PteGlu markedly increased by approximately 30 times. When PteGlu was given, the bile secretion of nonmethylated tetrahydrofolates markedly increased by 15-27 times, whereas that of 5-CH3-H4PteGlu increased by approximately 7 times. The results suggest that oxidized folates may be one of the sources for bile nonmethylated tetrahydrofolates. It is concluded that nonmethylated tetrahydrofolates in bile play an important role in folate homeostasis through enterohepatic circulation, together with 5-CH3-H4PteGlu.

Animals↗
PubMed1995

Effects of folic acid and pyrimethamine, a dihydrofolate reductase inhibitor, on intestinal absorption of folates in rats.

Oral co-administration of folic acid (pteroylglutamic acid, PteGlu) potentiates the decrease of plasma 5-methyltetrahydrofolic acid (5-CH3-H4PteGlu) concentration induced by pyrimethamine (PYR) in rats. To clarify the mechanisms of this potentiated decrease, we examined the effects of PteGlu and PYR on intestinal absorption of folates in rat jejunum loops, because plasma 5-CH3-H4PteGlu concentration is maintained by enterohepatic circulation of folates. The intestinal absorption of 5-[14C]CH3-H4PteGlu was inhibited by PteGlu, but not by PYR. The absorption of [3H]PteGlu was inhibited by reduced folates that exist in bile. These findings indicate that PteGlu competes with the bile reduced folates for the intestinal transport system. The bile secretion of reduced folates was also examined to observe the conversion of absorbed PteGlu to reduced folates in the liver in the presence of PYR. The bile secretion of reduced folates increased drastically after the administration of PteGlu alone, but not after the administration of PteGlu with PYR. These facts suggest that the absorbed PteGlu was not converted to reduced folates in the liver due to PYR. In conclusion, the potentiated decrease of plasma 5-CH3-H4PteGlu concentration must have resulted from a combination of the following two factors: the inhibition of reabsorption of bile reduced folates by PteGlu and the inhibition of PteGlu conversion to reduced folates in the liver by PYR.

Animals↗
PubMed1995

Impact of age-related alteration of plasma alpha 1-acid glycoprotein concentration on erythromycin pharmacokinetics in pigs.

Erythromycin (EM) pharmacokinetic variables were studied after IV administration of the drug (10 mg/kg of body weight) to 1-, 6-, and 15-day-old pigs. With advancing age, from 1 day to 15 days after birth, half-life of EM became shorter (3.0 hours to 1.4 hour), whereas apparent volume of distribution, total body clearance (CLt), and intrinsic clearance became greater: 0.68 to 3.28 (L/kg), 0.15 to 1.42 (L/h/kg), and 1.81 to 3.56 (L/h/kg), respectively. The percentage of plasma protein binding of EM decreased from 91 to 56%, correlating well with volume of distribution and CLt values. The altered binding percentage depended on plasma alpha 1-acid glycoprotein (AGP) concentration, but not on albumin concentration. With advancing age, plasma AGP concentration was markedly decreased from approximately 6,000 micrograms/ml to 700 micrograms/ml. Despite a twofold increase in intrinsic clearance with advancing age, CLt increased ninefold, implying that the decreased protein binding contributed to the increase of CLt more preferentially than did maturational development of elimination capacity. Therefore, the altered protein binding of EM attributable to the change in plasma AGP concentration could be a major causal factor of the age-related pharmacokinetic variables of EM in pigs.

Aging↗
PubMed1994

Identification of 5,10-methylenetetrahydrofolate in rat bile.

5,10-Methylenetetrahydrofolate (5,10-CH2-H4PteGlu) was identified as a major active reduced folate in rat bile using high-performance liquid chromatography with electrochemical detection (HPLC-ED). The identification of the folate derivative was based on the similarities in the retention-time profiles, electrochemical properties, UV absorption characteristics and demethylenation profiles of the bile folate and the synthetic standard. An HPLC-ED method was developed for the simultaneous determination of reduced folates including 5,10-CH2-H4PteGlu, tetrahydrofolate (H4PteGlu), 10-formyltetrahydrofolate (10-HCO-H4PteGlu) and 5-methyltetrahydrofolate (5-CH3-H4PteGlu) in rat bile. All peaks of the reduced folates in bile were separated using this method with a total retention time of less than 15 min. The detection limit was 0.01 ng/injection for H4PteGlu, 10-HCO-H4PteGlu and 5-CH3-H4PteGlu, and 0.02 ng/injection for 5,10-CH2-H4PteGlu at a signal-to-noise ratio of 3 and an injection volume of 100 microliters. Recoveries of synthetic folates from rat bile were higher than 90%. The distribution percentages of 5,10-CH2-H4PteGlu, H4PteGlu, 10-HCO-H4PteGlu and 5-CH3-H4PteGlu in rat bile were 29.6 +/- 7.2, 17.7 +/- 3.5, 24.4 +/- 6.5 and 28.2 +/- 7.1%, respectively, and total secretion rate of the bile reduced folates was 1514 +/- 663 ng/h (mean +/- S.D., n = 9).

Animals↗
PubMed1994

Antisecretory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene antagonism, on gastric acid secretion in the pig.

The antisecretory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene antagonism, on the hypersecretion of gastric acid stimulated by several secretagogues was examined in the pig. Goettingen miniature pigs with chronic gastric fistula were used. Intramuscular injection of carbachol (60 micrograms/kg), tetragastrin (50 micrograms/kg) or histamine (200 micrograms/kg)-induced gastric acid hypersecretion. Intraduodenal administration of DS-4574 (10 and 20 mg/kg) significantly inhibited both the hypersecretion induced by carbachol and that by tetragastrin. On the other hand, DS-4574 (50 mg/kg, intraduodenal) did not suppress histamine-induced hypersecretion. In the in vitro study, no effect on hog gastric K(+)-dependent ATPase activity was found at concentrations of DS-4574 from 10(-7) to 10(-4) M. These results were highly similar to those in the rat. The suppression of histamine release from histamine-containing cells in the gastric mucosa of the rat was concluded to be an antisecretory effect of DS-4574.

Adenosine Triphosphatases↗
PubMed1994

Alpha 1-acid glycoprotein-binding as a factor in age-related changes in the pharmacokinetics of trimethoprim in piglets.

This study examined the effects of plasma alpha 1-acid glycoprotein (AGP) on the protein binding and pharmacokinetics of trimethoprim (TMP) in piglets. The piglets were given 5 mg/kg of TMP intravenously at 1, 14 and 28 days after birth. The plasma AGP level was highest at day 1. Fourteen days after birth, the level decreased by about 90% of that at day 1. The level at 28 days was almost the same as that at 14 days. Plasma protein bindings of TMP depended on the AGP level but not on the albumin level. The percentage of plasma protein binding decreased from 85 to 45%, and the AGP level also decreased from 6,000 to 700 micrograms/ml. The altered protein binding of TMP affected pharmacokinetic parameters such as total body clearance (CLtot), distribution volume and therefore the elimination rate constant. These parameters correlated well with the percentage binding to plasma proteins. Maturational development in the capacity to eliminate TMP was also indicated by the increase in total body clearance of unbound drug (CLtotub), which directly reflects the elimination capacity of the body. However, its contribution to the increase in CLtot was considered not to be large. CLtotub increased twofold 14 days after birth, whereas CLtot increased about ninefold. The increase in CLtot therefore, may result from both the maturational development in elimination capacity and the AGP-dependent decrease in plasma protein binding. It is concluded that the decrease in plasma AGP level observed in piglets is one of major factors affecting the pharmacokinetics of TMP.

Aging↗
PubMed1994

Pharmacokinetics and bioavailability of folic acid and plasma levels of bioactive folates after folic acid administration to pigs.

After intravenous (1 mg/kg body weight), intramuscular (1 mg/kg body weight) and oral (1 and 50 mg/kg body weight) administration of folic acid (FA) to pigs, plasma levels of FA, tetrahydrofolic acid (THF), 5-methyltetrahydrofolic acid (5MF) were determined by using high-performance liquid chromatography. The pharmacokinetic profile of plasma FA after oral administration indicated an absorption rate-limited elimination, i.e., so called 'flip-flop' phenomenon. The bioavailability of FA was quite low after a high oral dose (F = 0.01), in contrast to a high value after intramuscular administration (F = 0.95). The plasma levels of biologically active, reduced forms of folates (THF and 5MF) were significantly increased over their basal levels after IV and IM administration to FA. The levels of these active folates were not increased after oral administration of a similar dose of FA. A 50 times higher dose was required to increase the active folates to the levels observed after IV and IM administration.

Administration, Oral↗
PubMed1994

Simultaneous determination of tetrahydrofolate, 10-formyltetrahydrofolate and 5-methyltetrahydrofolate in rat bile by high-performance liquid chromatography with electrochemical detection.

This report describes an analytical method for the measurement of tetrahydrofolate (H4PteGlu), 10-formyltetrahydrofolate (10-HCO-H4PteGlu) and 5-methyltetrahydrofolate (5-CH3-H4-PteGlu) in rat bile by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). After diluting the bile sample with 0.2% sodium ascorbate solution, the sample was analyzed under the following conditions; (a) phenyl bonded phase column as an analytical column; (b) mobile phase consisting of 20 mM acetate buffer (pH 5.0) containing 0.1 mM EDTA; (c) an applied ECD potential of +300 mV; (d) 0.8 ml/min of flow rate. Under the above conditions, peaks of H4PteGlu, 10-HCO-H4PteGlu and 5-CH3-H4PteGlu in rat bile were well separated on the ECD-chromatogram. Detection limits of H4PteGlu, 10-HCO-H4PteGlu and 5-CH3-H4PteGlu were 0.13, 0.11 and 0.10 ng/ml, respectively, at S/N = 3. Bile excretion rates for H4PteGlu, 10-HCO-H4PteGlu and 5-CH3-H4PteGlu, which were analyzed by this method in rats, were 314 +/- 181, 321 +/- 179 and 449 +/- 198 ng/hr, respectively. Bile concentrations of the folates were more than 5,000 times higher than the detection limits for this method. This HPLC-ECD method is, therefore, a useful tool for bile folate analysis.

Animals↗
PubMed1993

Identification of 10-formyltetrahydrofolate, tetrahydrofolate and 5-methyltetrahydrofolate as major reduced folate derivatives in rat bile.

Reduced folate derivatives in rat bile were examined using high-performance liquid chromatography with electrochemical detection (HPLC-ED). Three peaks of folate compounds were observed on the chromatograms. From the retention-time profiles and hydrodynamic voltammograms, and the profiles of ultraviolet (UV) absorbance spectra obtained by HPLC with photodiode array detection, these 3 peaks were identified as 10-formyltetrahydrofolate (10-HCO-H4PteGlu), tetrahydrofolate (H4PteGlu) and 5-methyltetrahydrofolate (5-CH3-H4PteGlu). The rates of bile secretion of 10-HCO-H4PteGlu, H4PteGlu and 5-CH3H4PteGlu were 314 +/- 181, 321 +/- 179 and 449 +/- 198 ng/h (mean +/- S.D.), respectively. 10-HCO-H4PteGlu and H4PteGlu together wtih 5-CH3-H4-PteGlu are found to be the major folate derivatives in rat bile. The nonmethylated folates, 10-HCO-H4PteGlu and H4PteGlu, may also play an important role in folate homeostasis.

Animals↗
PubMed1992

Transdermal delivery and intramuscular injection of trimethoprim/sulphadiazine in sucking piglets.

The pharmacokinetics of a combination of trimethoprim (TMP) and sulphadiazine (SDZ) after topical application to sucking piglets was compared with the pharmacokinetics after intramuscular injection. A long-lasting and fairly constant SDZ/TMP concentration ratio in plasma was obtained after topical application. The mean plasma concentration of TMP ranged from 0.091 to 0.17 micrograms/ml and that of SDZ from 0.72 to 1.1 micrograms/ml for at least 24 h. TMP and SDZ had different half-lives after intramuscular injection. Transdermal delivery of a combined preparation of TMP/SDZ may be usable for colibacillosis of sucking piglets, although the bioavailability of the drugs is poor.

Administration, Cutaneous↗
PubMed1991

Tetrahydrofolic acid as the principal congener of plasma folates in pigs.

Concentrations of pig plasma folates were determined by a high-performance liquid chromatography with an electrochemical detector (HPLC-ECD). Tetrahydrofolic acid (THF) and 5-methyltetrahydrofolic acid (5-MF) were found to be the plasma folates. The concentration of THF (10.3 +/- 4.3 ng/ml) was significantly higher than that of 5-MF (3.5 +/- 1.0 ng/ml). The sum of the THF and 5-MF concentrations determined by the HPLC-ECD analysis in Göttingen miniature pigs was comparable to the total folate concentration of the same plasma sample determined by a radioligand assay. No or only trace amounts of THF were found in the plasma of the rats, mice, rabbits, dogs, cows, horses, or humans. Although 5-MF is generally recognized as the only principal plasma folate in many species, THF may be the principal congener with 5-MF as a secondary congener in the pig.

Animals↗
PubMed1990

Oral dosage regimen in the nonlinear pharmacokinetics of sulphadimethoxine in pigs.

An oral high dosage regimen of sulphadimethoxine (SDM) was examined in pigs. The dose (50 mg/kg) in the therapeutic range, showed nonlinear pharmacokinetics, and administered by drench once a day for 4 days. The unbound plasma concentration-time profile was compared with that of the dosage regimen based on nonlinear pharmacokinetics, where a pharmacokinetic model and parameters were used except for the first order absorption rate constant (ka) and bioavailability (F). F and ka were obtained from oral and intravenous administration of 20 and 10 mg/kg of SDM. The unbound plasma concentration was observed almost within the setting range by the dosage regimen through the experimental period. This result suggested that the dosage regimen, based on the nonlinear pharmacokinetic model, resulted in an appropriate effect in the clinical use.

Absorption↗