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Biomedical subjects

I Horikoshi

Publications and source records attributed to I Horikoshi.

At least 55 records · Page 3Linked to original sources
PubMed1990

First-pass metabolism of acetaminophen in rats after low and high doses.

The first-pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg-1 doses by intra-arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first-pass effect after oral administration (oral extraction) was extensive (Eo = 0.34-0.50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0.33-0.50). At higher doses (150 and 300 mg kg-1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose-dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.

Acetaminophen↗
PubMed1990

Disposition of phenytoin in analbuminemic rats.

The disposition characteristics of phenytoin were investigated in analbuminemic rats to study the effect of plasma protein binding on phenytoin disposition. Blood and plasma phenytoin concentration determinations, measurement of plasma protein phenytoin binding, and whole-body autoradiography were performed after intravenous bolus injection of 10 mg kg-1 of phenytoin. When plasma phenytoin was assayed, total body phenytoin clearance (CL) was faster and its apparent volume of distribution (Vd) greater in the analbuminemic rats in comparison to the controls. The plasma protein binding of phenytoin was significantly lower in the analbuminemic rats, suggesting the disposition characteristics of phenytoin were altered in the presence of low plasma albumin concentrations due to reduced plasma phenytoin protein binding. On the other hand, when blood phenytoin levels were analyzed, no difference in CL and a less pronounced difference in Vd were noted between the two groups of rats. The red blood cell-to-plasma phenytoin concentration ratios were greater in analbuminemic rats, suggesting that the distribution of phenytoin into red blood cells was greater in the mutant rats.

Animals↗
PubMed1990

Targeting behavior of hepatic artery injected temperature sensitive liposomal adriamycin on tumor-bearing rats.

Temperature sensitive liposomal Adriamycin (LADM) was injected into the hepatic artery of rats bearing implanted hepatic tumors. Two hours after the injection, the liver was heated at 42 degrees C and maintained for six minutes at that temperature using local hyperthermia. Blood samples were taken at regular intervals until 8 hours after injection, at which time the animals were sacrificed and the drug distribution in the tissues was examined. Results indicate that the Adriamycin was released from the liposome, with the drug concentration in circulation peaking at 30 minutes after heating. High drug levels (25.2 micrograms/g of wet tissue) in the tumor and high tumor/liver Adriamycin level ratios (TLAR; 4.1) were found. The drug levels and the TLAR of the liposomal Adriamycin injection combined with heating (LADM H) were significantly different from those of the same dose of aqueous Adriamycin with heating (ADM H) or aqueous Adriamycin (ADM) and LADM without heating. The experiment shows that the LADM is cleared from the liver slowly, and when hyperthermia treatment at phase-transition temperature of the liposome is performed, the drug level in an implanted hepatic tumor is increased, and in the parenchyma is decreased. The results imply that targeting the hepatic tumor in this way may be an effective therapeutic method, and the drug release from the liposome may be controlled externally. This method appears promising for clinical practice.

Animals↗
PubMed1990

Inhibitory effects of galloylglucose on nicotinamide adenine dinucleotide dehydrogenases of the aerobic respiratory chain of Escherichia coli.

The effects of pentagalloylglucose (1,2,3,4,6-penta-O-galloyl-beta-D-glucose) on the aerobic electron transport system of Escherichia coli were studied. The activity of nicotineamide adenine dinucleotide (NADH) reductase was inhibited by pentagalloylglucose, but the activities of succinate dehydrogenase, D-lactate dehydrogenase, and ubiquinol-1 (Q1H2) oxidase were not susceptible to the inhibitor. Because the presence of two kinds of NADH dehydrogenase in respiratory chain of Escherichia coli has been reported, we examined the effect of galloylglucose independently on both NADH dehydrogenases. Pentagalloylglucose is potent and specific inhibitor of both NADH dehydrogenases. One of the NADH dehydrogenases (NADH dh II) is more sensitive to the inhibitor than the other (NADH dh I).

Aerobiosis↗
PubMed1990

[Effects of cepharanthine on liposomal permeability and size].

Effects of cepharanthine, one of membrane-stabilizing agents, on membrane permeability and on liposomal size were examined. When cepharanthine was added to the lipid before liposome formation, the size of liposome increased and the permeability did not change. On the other hand, when cepharanthine was added to the liposome suspension after liposome formation, no effect was found on liposomal size but the membrane permeability increased and lag time of initial leak of 5 (& 6)-carboxyfluorescein reduced dose-dependently.

Alkaloids↗
PubMed1989

Enhancement of phenytoin binding to tissues in rats by heat treatment.

Phenytoin binding to heat-treated tissue homogenates has been examined to characterize the phenytoin binding to tissues. The binding to the heat-treated tissue homogenates was enhanced in all tissues studied compared with controls. The heating might produce the changes in conformation of proteins in tissues and then enhance phenytoin binding to tissue homogenates.

Animals↗
PubMed1989

The effects of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose on rat liver mitochondrial respiration.

The inhibitory effects of pure galloylglucose (1,2,3,4,6-penta-O-galloyl-beta-D-glucose) on the respiratory chain of rat liver mitochondria were investigated. The respiratory control ratio (RCR) decreased by 50% on addition of 20 microM pentagalloylglucose to highly coupled mitochondria, but the adenosine-5'-diphosphate/oxygen (ADP/O) ratio decreased only slightly. The RCR disappeared and the ADP/O ratio could not be measured at concentrations of pentagalloylglucose above 30 microM. On the other hand, the uncoupler-induced oxygen consumption was also inhibited. These findings suggest that pentagalloylglucose at low concentrations inhibits the electron transport system to decrease the RCR, but scarcely impairs the membrane, practically retaining the coupled reaction, while at high concentrations it impairs the structural integrity of the mitochondrial membrane. Pentagalloylglucose competitively inhibited succinate dehydrogenase activity, and noncompetitively inhibited reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase and ubiquinol-1 oxidase activities of submitochondrial particles (SMP). However, it did not show significant inhibition of the cytochrome c oxidase activity of SMP. It is thus concluded that pentagalloylglucose, which is the lowest-molecular-weight component of tannic acid, exerts its effect on mitochondrial respiration and oxidative phosphorylation through action on the membrane and on succinate dehydrogenase, NADH dehydrogenase and cytochrome bc1 complex of mitochondria.

Animals↗
PubMed1989

Inhibitory effects of tetragalloylglucose on the complex II of mitochondrial respiratory chain of Ascaris muscle.

The effects of tetragalloylglucose (1,2,3,6-tetra-O-galloyl-beta-D-glucose) on purified complex II (succinate-ubiquinone oxidoreductase) of the mitochondrial electron transport system of Ascaris muscle were studied. Both succinate-ubiquinone-1 (Q1) oxidoreductase, and succinate dehydrogenase measured with 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) in the presence of phenazine methosulfate (PMS) were inhibited by tetragalloylglucose. The inhibitions of both reductase activities of complex II were of competitive type, and the inhibitor constant (Ki) for Ascaris complex II (148 nM) was lower than that for rat liver complex II (1.5 microM). Thus, Ascaris complex II is much more sensitive to this inhibitor than the mammalian counterpart.

Animals↗
PubMed1989

[Basic study on hepatic artery chemoembolization and tumor selective drug targeting by temperature-sensitive liposome with local hyperthermia].

Temperature-sensitive liposome entrapping adriamycin (L-ADM) was administered into the hepatic artery of hepatic tumor-bearing rats. The embolization of the hepatic artery with liposome and bio-distribution of ADM were examined. ADM concentration in blood showed a peak at 30 min after local heating on tumor (the heating had been performed for 6 min at 41-42 degrees C 2 hr. after injection). The value at the peak was about 3 times higher than that just before heating. ADM administered in liposomal form showed a high accumulative property to tumor with heating; ADM concentration in tumor 8 hr. after administration of ADM in liposomal form was about 5 times higher than that in liver and about 30 times higher than that in the heart, and about 20 times higher than that in tumor after administration in free form.

Animals↗
PubMed1988

Pharmacokinetics of two rectal dosage forms of ketoprofen in patients after anal surgery.

Two kinds of dosage forms of commercially available suppositories containing ketoprofen (KP), fatty suppositories (FS) and gelatin capsulated suppositories (GCS), were administered to patients immediately after anal surgery, and results obtained were compared. No difference was found in each corresponding pharmacokinetic parameter of the two dosage forms. However, when these parameters were compared with those from healthy subjects, significant differences were found in the values of peak level (Cmax), peak time (Tmax) and terminal phase half-life (t1/2). Cmax decreased by one half, and Tmax and t1/2 increased two and four times longer, respectively, those from healthy subjects. The absorption rate constant (ka) in patients was significantly (p less than 0.01) smaller than that in healthy subjects. However, the distribution volume/bioavailability (Vd/F), elimination rate constant (kel), and area under the curve (AUC) differed only slightly. Consequently, the flip-flop phenomena could be seen in the time profiles of plasma KP concentration of patients. These results suggested that the rectal suppository of KP should be administered with care, especially in the patients operated on under spinal anesthesia.

Adult↗
PubMed1988

Factors causing age-dependent changes in phenytoin tissue and serum binding in rats.

The factors that cause age-dependent changes in phenytoin tissue and serum protein binding in rats were studied. It was confirmed that the age-dependent changes in the concentration of tissue constituents to which phenytoin bound mainly governed the change in phenytoin tissue binding. The concentration of the tissue constituents, protein and phospholipid, was changed by the water content in tissues in the growth process of rats. The increase in serum protein binding of phenytoin in the growth process of rats was caused by changes in both serum albumin concentration and binding parameters of phenytoin to serum albumin. The changes in binding parameters of phenytoin to serum albumin were led by those in the molar rations of free fatty acids to albumin.

Aging↗
PubMed1987

Age-dependent changes in phenytoin tissue distribution in rats.

Age-dependent changes of phenytoin disposition in rats were studied following intravenous administration of 5,5-[4-14C]-diphenylhydantoin to 1-d, 1-, 3- and 8-week-old rats. The distribution volumes changed similarly to those of warfarin in the growth process of rats. The lower clearances in infant and young rats were considered to be caused by the undeveloped liver function to metabolize phenytoin. The changes of distribution volumes in the growth process of rats were assumed to be based upon not only the changes in blood free fractions but also other factors. In any aged rats, the muscle largely contributed to the distribution of phenytoin in the body and the Kp values in the muscle decreased in the growth process of rats. This change of phenytoin transfer to the muscle affected the decrease of distribution volumes of phenytoin in 8-week-old rats and the distribution volumes of brain, lung and liver in infants and young rats were greater than those in adult rats. The Kp value in the lung in 8-week-old rats was smaller than the values in 1-d, 1- and 3-week-old rats and there was no significant difference in the Kp values in the liver among the 4 ages. These results were different from those in warfarin reported previously and suggested that warfarin and phenytoin bind different macromolecules in the liver and the lung.

Aging↗
PubMed1987

Age-dependent change in warfarin distribution volume in rats: effect of change in extracellular water volume.

The pharmacokinetics of insulin was studied following intravenous administration of 14C-inulin to 1-d, 1-, 3- and 8-week-old rats. The distribution volume of inulin varied 2-fold, from 689 ml/kg in 1-d-old rats to 340 ml/kg in 8-week-old rats in the growth process of rats. This result was similar to that of warfarin and there was a statistically significant correlation between the distribution volume of warfarin and inulin (r = 0.984, p less than 0.02). In the growth process of rats, the Kp values of warfarin in muscle, which play an important role in the distribution kinetics of warfarin changed in parallel with those of inulin. These results and pharmacokinetic considerations indicated that in warfarin, which is highly bound to serum protein and shows a small distribution volume, the change in the distribution volume in the growth process of rats following administration of a pharmacologically realistic dose (1 mg/kg) is led by the change in the extracellular volume of tissues and that the change in serum protein binding of warfarin might play a minor role in the change in the distribution volume in the growth process.

Aging↗
PubMed1987

Age-dependent changes in phenytoin tissue bindings in rats: comparison between in vivo and in vitro tissue-to-blood partition coefficients (Kp values) of phenytoin.

Age-dependent changes in phenytoin tissue bindings in rats were investigated by equilibrium dialysis using serum and 10% tissue (brain, lung, liver, kidney and muscle) homogenates. All percentages of phenytoin bound to serum and tissue homogenates were independent of the initial phenytoin concentration (2 to 25 micrograms/ml) in 1-d, 1-, 3- and 8-week-old rats. The percentages bound to serum, brain, liver, kidney and muscle in newborn rats (1-d-old rats) were lower than those in 8-week-old rats and the percentages bound increased gradually in the growth process. However, those in lungs were constant in all ages of rats. It was assumed that the age-dependent changes in phenytoin tissue binding were caused by the changes in the quantities of tissue constituents to which phenytoin bound in the growth process. Tissue-to-blood partition coefficients (Kp values) were calculated from in vitro tissue binding data and the pH-difference across the cell membrane. These Kp values were in good agreement with the in vivo Kp values reported previously. It was concluded that the age-dependent changes in phenytoin tissue distribution were caused by the age-dependent changes in phenytoin binding to blood constituents and tissues but that the change of phenytoin blood binding contributed to the age-dependent changes in Kp values of phenytoin more than to phenytoin tissue binding and consequently the Kp values of phenytoin decreased as rats grew.

Aging↗