Novel transdermal targeting in steroid therapy: evaluation of PK/PD profiles using an animal model of rheumatoid arthritis.
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Administration, Cutaneous↗
Biomedical subjects
M Komuro
Publications and source records attributed to M Komuro.
First-pass of GTS-21 on canine gut wall and liver determined by portal-systemic concentration difference.
To clarify the cause of the canine individual variability of plasma concentration after oral administration of GTS-21 [(E)-3-(2,4-dimethoxybenzylidene)-3,4,5,6-tetra-hydro-2,3'-bipyridine dihydrochloride], we evaluated the absorption ratio (F(A)), intestinal availability (F(G)), and hepatic availability (F(H)). The bioavailability (F) was evaluated from the ratio of the area under the plasma concentration versus time curves after oral and intravenous administration. Three isoflurane anaesthetised dogs were fitted with an electromagnetic flow probe attached to the portal vein and cannulated through the portal and the femoral veins. After intraduodenal administration of GTS-21, both plasma concentrations were determined simultaneously. F(A) x F(G) was calculated from the portal-systemic concentration difference taking into consideration the blood-plasma partition ratio. F(A) was calculated from the residual drug contents of the small intestine. F(H) was calculated by dividing F by F(A) x F(G). The F values were 0.072, 0.021, and 0.037, indicating an individual variability of ca. threefold. The F(A) values were close to 1, and the F(G) values ranged from 0.449 to 0.461. Accordingly, the F(H) values were estimated at 0.170, 0.047, and 0.083. GTS-21 was completely absorbed but lost by first-pass effects of passage through the gut wall and liver. The first-pass effect of liver is larger than that of the gut wall, and dominates the individual variability in plasma concentration.
Animals↗
The effect of repeat administration of GTS-21 on mixed-function oxidase activities in rat.
The effect of repeat administration of GTS-21 on hepatic microsomal enzymes was determined in rats administered the drug at levels of 3, 60 and 300 mg/kg/day for 7 days. Liver weight and cytochrome P450 (CYP) contents were not changed. Cytochrome b5 contents were increased at the mid and high doses of GTS-21, as the contents increased with increasing dose, but were unchanged at the low dose. Five selective activities of CYP isoforms, acetanilide hydroxylase (CYP1A2), tolbutamide hydroxylase (CYP2C6), dextromethorphan O-demethylase (CYP2D1), p-nitrophenol hydroxylase (CYP2E1) and erythromycin N-demethylase (CYP3A) were examined. Enzyme activities were changed only at the highest dose; the activity of CYP1A2 was increased by 71% and the activities of CYP2C6 and CYP2D1 were decreased by 37 and 19%, respectively. At low and mid doses of GTS-21, all activities were unchanged. These data indicate that GTS-21 is not a strong modulator of the mixed-function oxidase system.
Alzheimer Disease↗
Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease.
1. GTS-21, a novel drug for Alzheimer's disease, is currently under clinical development. In the current study, the metabolism and disposition of GTS-21 have been evaluated in rat and dog after single oral and intravenous administration. 2. Following oral administration of [14C]GTS-21 to rat, radioactivity was primarily excreted in the faeces (67%) via the bile with possible enterohepatic circulation. Urinary excretion of radioactivity in rat and dog was 20 and 19% respectively. 3. GTS-21 was rapidly and extensively absorbed after oral administration and rapidly cleared from plasma. The maximum concentration ratio of GTS-21 to total radioactivity in plasma was low, indicating first-pass or pre-systemic biotransformation. 4. In rat, GTS-21 showed linear pharmacokinetics over doses ranging from 1 to 10 mg/kg with an absolute bioavailability of 23%. In dog, the absolute bioavailability was 27% at an oral dose of 3 mg/kg. 5. GTS-21 was O-demethylated to yield compounds that were then subject to glucuronidation. Three of the metabolites in rat urine were isolated and characterized as 4-OH-GTS-21, 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. The major urinary metabolites were 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. 6. In vitro chemical inhibition of cytochrome P450 in human liver microsomes indicated that CYPIA2 and CYP2E1 were the isoforms primarily responsible for the O-demethylation of GTS-21, with some contribution from CYP3A.
Alzheimer Disease↗
Effects of high-fat diet intake on glucose uptake in central and peripheral tissues of non-obese rats.
We previously demonstrated that plasma glucose concentration was higher while plasma insulin concentration was lower in rats fed a high-fat diet. In the present study, we examined the effects of high-fat diet on glucose uptake in central and peripheral tissues in non-obese rats. Forty male Sprague-Dawley rats were fed high- or low-fat diets for 4 wk. Body weight and body fat accumulation were not different between the two diet groups after 4 wk. Glucose uptake in the skeletal muscles and adipose tissues, estimated by the 2-deoxy-D-glucose method, was lower in the rats fed the high-fat diet than that in the rats fed the low-fat diet, whereas uptake in the liver and pancreas did not differ between the two groups. Glucose uptake in the hypothalamus and cortex was higher in the high-fat diet group as compared with that in the low-fat diet group. These results suggest that increased plasma glucose levels in rats fed the high-fat diet were caused by a decrease in glucose uptake in the skeletal muscles and adipose tissues. Reduced plasma insulin level in the high fat diet group with no difference in glucose uptake in the pancreas may be due to increased sympathetic activity in the pancreas resulting from the increased glucose uptake in the brain regions involved in autonomic functions.
Adipose Tissue↗
Establishment of Epstein-Barr virus-positive human gastric epithelial cell lines.
We have established two Epstein-Barr virus (EBV)-positive cell lines, GT38 and GT39, derived from human gastric tissues of two patients bearing gastric carcinoma. Both cell lines were positive for cytokeratin, an epithelial marker, but not for lymphocyte-related markers. Unlike GT39 cell line, GT38 cells lacked the property of contact inhibition. EBV genome was detected in both cell lines. The cell lines were positive for latent membrane protein 1, and EBV-determined nuclear antigen 1 (EBNA1). EBNA2 was also detected in GT38. These cell lines should be useful for studying the interaction of EBV with gastric epithelial cells and its role in gastric carcinogenesis.
Cell Line↗
The formation of desethyl-piperacillin from piperacillin by human liver S9 in vitro.
Piperacillin (PIPC) has been used as one of the most useful beta-lactam antibiotics over the past 10 years. The metabolism of PIPC has been thoroughly investigated and it has been recognized that PIPC gives few metabolites in laboratory species or humans. Recently, an active metabolite, desethyl-piperacillin (DEt-PIPC), was detected in human plasma and urine after PIPC administration. In the current study, human tissues were obtained from organ donors (n = 3) and subcellular fractions (S9) were prepared. The time course of metabolism by S9 mix from liver, kidney cortex, and kidney medulla was then determined using 0.5 mM PIPC. For comparative purposes, rat liver S9 were also prepared and incubated with PIPC under the same conditions. DEt-PIPC was formed by human liver S9 mix from all three specimens studied, with the rate varying approximately eightfold. No DEt-PIPC was detected in any of the incubations with rat liver S9 mix (n = 3) and kidney S9 mix (n = 3) prepared from either the cortex or medulla. In summary, these data suggest that the formation of the unique human metabolite, DEt-PIPC, can be predicted by in vitro studies with human tissues and that this metabolite is formed predominantly by the liver.
Adult↗
[Our HPN guidance].
As many medical services, medicines and instruments are provided for home treatment, the needs of home care are on the increase. The support of the patient's family is required to perform HPN and provide care. There are many problems and fears of self-care and one's own performance HPN. We attempt to make HPN guidance. The selected key person in patient's family is directed by the same nurse using schema and illustrations on HPN. The items to be acquired the theory and practice are assessed together. HPN timetable is done according to the key person's schedule. Before discharge, the patient and family contact with the visiting care nurse team (visiting nurse, doctor, outpatient clinic). The guidance and practice of HPN according to the schedule or offering it to the patient and family are readily accepted. It is important to remove the problems and fears associated with establishing a medical support system.
Aged↗
Gene expression of insulin signal-transduction pathway intermediates is lower in rats fed a beef tallow diet than in rats fed a safflower oil diet.
To elucidate the effects of dietary fatty acid composition on the insulin signaling pathway, we measured the gene expression of the earliest steps in the insulin action pathway in skeletal muscle of rats fed a safflower oil diet or a beef tallow diet. Rats were meal-fed an isoenergetic diet based on either safflower oil or beef tallow for 8 weeks. Both diets provided 45%, 35%, and 20% of energy as fat, carbohydrate, and protein, respectively. Insulin resistance, assessed from the diurnal rhythm of plasma glucose and insulin and the oral glucose tolerance test (OGTT), developed in rats fed a beef tallow diet. Body fat content was greater in rats fed a beef tallow diet versus a safflower oil diet. The level of insulin receptor mRNA, relative expression of the insulin receptor mRNA isoforms, and receptor protein were not affected by the composition of dietary fatty acids. The abundance of insulin receptor substrate-1 (IRS-1) and phosphatidylinositol (PI) 3-kinase mRNA and protein was significantly lower in rats fed a beef tallow diet versus a safflower oil diet. We conclude that long-term feeding of a high-fat diet with saturated fatty acids induces decrease in IRS-1 and PI 3-kinase mRNA and protein levels, causing insulin resistance in skeletal muscle.
Actins↗
Diurnal rhythm of plasma insulin and glucose in rats made obese by a high fat diet.
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Adipose Tissue↗
Beef tallow diet decreases uncoupling protein content in the brown adipose tissue of rats.
The effects of dietary fats consisting of different fatty acids on the content of mitochondrial uncoupling protein in the interscapular brown adipose tissue were studied in rats. Sprague-Dawley male rats were meal-fed an isoenergetic diet based on either beef tallow or safflower oil for nine weeks. The gain in body weight during the experimental period did not differ between the two dietary groups. The weight of the brown adipose tissue was similar in the two dietary groups, whereas the weight of the abdominal white adipose tissue was larger in rats fed the beef tallow diet. The content of mitochondrial uncoupling protein in brown adipose tissue was lower in the beef tallow diet group than in the safflower oil diet group without differing mitochondrial mass between the two dietary groups. These results suggest that, in rats, a beef tallow diet reduces the content of uncoupling protein in brown adipose tissue, resulting in lower diet-induced thermogenesis as compared to a safflower oil diet.
Adipose Tissue, Brown↗
Application of chemical cytochrome P-450 model systems to studies on drug metabolism--VIII. Novel metabolism of carboxylic acids via oxidative decarboxylation.
The oxidative decarboxylation of carboxylic acids by the chemical cytochrome P-450 model and rat liver microsomal systems was investigated. In the chemical system using meso-tetrakis(pentafluorophenyl)porphyrin iron chloride [Fe(TPFPP)Cl] with iodosylbenzene (PhIO), alpha-arylcarboxylic acids and alpha,alpha,alpha-trisubstituted acetic acids are converted to the corresponding one-carbon-reduced alcohol (I) and carbonyl derivatives (II) via oxidative decarboxylation. These products were then used as standards to identify the metabolites in vivo and in vitro. Biliary excretion of Ia and IIa in bile duct-cannulated rats after oral administration of ketoprofen amounted to 0.22 and 0.03% of the dose, respectively. In the case of indomethacin, Ib and IIb were detected as metabolites in the rat liver microsomal system, in yields of 2.8 and 0.29%, respectively. Further, the yields of Ib and IIb were decreased in the presence of SKF-525A. Thus, these metabolites were formed by cytochrome P-450-dependent reactions. Metabolites Ia, Ib, IIa and IIb had moderate to strong inhibitory activities on arachidonic acid-induced platelet aggregation and cyclooxygenase activity in vitro, comparable to those of the parent compounds.
Animals↗
Inhibition of the renal excretion of tazobactam by piperacillin.
A 1:4 by weight of combination of tazobactam, a new beta-lactamase inhibitor, and piperacillin, is now under development in Japan. After bolus iv administration of the combination to beagle dogs, piperacillin both significantly raised the area under plasma concentration time curve (AUC0 approximately infinity) and significantly decreased the total body clearance (Cltot) of tazobactam. The percentage binding of tazobactam and piperacillin to dog and human serum protein was the same for the combination as for the individual compounds. Piperacillin significantly decreased the renal clearance (Clr) and the clearance ratio (Cr) of tazobactam in dogs. Further, probenecid significantly decreased Clr of both tazobactam and piperacillin, and the Cr of tazobactam and piperacillin approximately reached unity. These results indicate that piperacillin inhibits the renal excretion of tazobactam. Both tazobactam and piperacillin are secreted by a tubular anion transport system which is identical to the probenecid secretion system.
Animals↗
Cellular variations in heterotrimeric G protein localization and expression in rat pituitary.
The secretory cells of the anterior pituitary are regulated by hypothalamic and target endocrine hormones. In many cases, intracellular signaling after ligand binding to cell surface receptors is mediated by heterotrimeric G proteins. In this study, cells from the rat pituitary and two pituitary cell lines (GH3 and AtT-20 cells) were doubly labeled by immunofluorescence with specific rabbit antibodies to the alpha-subunits of G proteins (Gs, Gi1-3, or Gq) and monoclonal antibodies against pituitary hormones (GH, PRL, beta LH, beta TSH, or beta FSH) to identify specific cell types. Gs, Gi, and Gq were detected in all secretory types, but differences were found in their levels of expression and cellular distribution. The cell periphery was the predominant site of localization of all these G proteins. In addition, both Gi3 and at least one member of the Gq family were seen by immunofluorescence on intracellular sites typical of the Golgi region. By immunogold labeling, alpha i3 was localized to membranes of Golgi cisternae in sections of rat pituitary and GH3 cells, where it was concentrated on the cis-side of the Golgi stack. These findings demonstrate that G proteins are widely expressed in anterior pituitary cells and further support a role for Gi alpha 3, and possibly Gs, in intracellular membrane trafficking.
Animals↗
Ligand-induced internalization of the epidermal growth factor receptor is mediated by multiple endocytic codes analogous to the tyrosine motif found in constitutively internalized receptors.
Ligand-induced internalization of epidermal growth factor (EGF) receptors via a high affinity saturable pathway requires sequences located in the carboxyl terminus distal to the tyrosine kinase domain. Three regions were found to contain endocytic motifs as defined by their ability to restore internalization function to EGF receptors truncated at the distal border of the kinase domain at residue 958. Deletional analysis identified the sequence 996QQGFF as essential for function of the region encompassing residues 993-1022. QQGFF and the deduced sequence of the region encompassing residues 973-991 (973FYRAL) could effectively replace the endogenous endocytic code of the transferrin receptor (YTRF). FYRAL and YTRF were less active than QQGFF when substituted into region 993-1022 of the EGF receptor, but a synthetic sequence (NNAYF), predicted to have structural features of a tight turn, effectively replaced QQGFF for EGF receptor internalization. Whereas EGF receptor sequences functioned effectively in the transferrin receptor, function of these sequences in the EGF receptor was strictly dependent on intrinsic tyrosine kinase activity as demonstrated kinetically and by immunofluorescence using semithin cryosections. Ligand-dependent endocytosis and down-regulation of the EGF receptor thus require multiple sequence motifs that are exchangeable between ligand-dependent and -independent receptors, but that require intrinsic tyrosine kinase activity for function in the context of the EGF receptor.
Amino Acid Sequence↗
[The partial resection of lung with MULTIFIRE ENDO GIA 30 under the thoracoscopy].
MULTIFIRE ENDO GIA 30 was a newly auto suture developed by US surgical c.o., A 27-year-old man was admitted for right spontaneous pneumothorax in our hospital. We performed the partial resection of lung with this new auto suture under the thoracoscopy. Condition of patient after operation was very good, and he could discharge in short hospitalization. We concluded that this new auto suture was entirely reversible and safety.
Adult↗
Identification of urinary metabolites of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in rat, rabbit and dog.
The metabolism of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) in rat, rabbit and dog was studied. The urine of animals dosed with 14C-KC-764 was extracted with ethyl acetate after treatment with beta-glucuronidase and arylsulfatase. The metabolites were purified by TLC and HPLC from the extract. Unchanged KC-764 and 16 metabolites were isolated and their structures were identified or proposed by NMR and MS spectrometry. The metabolism of KC-764 took place by the oxidation of the tetrahydropyridine ring, 6,7-position and 2-methyl group of the pyrazolopyridine ring, and their combinations. The oxidation of the tetrahydropyridine ring was predominant in dog, whereas the oxidation of the pyrazolopyridine ring was more important in rabbit. Rat produced the various metabolites by their combination. 6-Oxo and 6-ureido derivatives of the tetrahydropyridine ring were common major metabolites in all animal species studied.
Animals↗
Pharmacokinetics of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in laboratory animals.
KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo [1,5-a]pyridine CAS 94457-09-7) and its metabolites in serum and urine were determined after intravenous and oral administration in mice, rats, rabbits and dogs at a dose of 5 mg/kg. KC-764 was rapidly eliminated from serum in all species. The biological half-lives of unchanged KC-764 after intravenous administration in mice, rats, rabbits and dogs were 1.31, 0.29, 1.94 and 1.20 h, respectively. 2-Methyl-3-(1,4,5,6-tetrahydro-6-oxonicotinoyl)pyrazolo-[1,5-a]pyr idine was a common major metabolite in serum of all species, although 6,7-dihydro-6,7-dihydroxy-2-methyl-3-(1,4,5,6- tetrahydro-6-oxonicotinoyl) pyrazolo-[1,5-a]pyridine (M-8) was more abundant in rabbits. Urinary recovery of unchanged KC-764 was as low as 0.4-2.2% in all species. The major urinary metabolite was 2-methyl-3-(1,4,5,6-tetrahydro-6-ureidonicotinoyl)pyrazolo-[1,5-a] pyridine in mice, rats and dogs, but M-8 was in rabbits. KC-764 was rapidly and well absorbed by oral administration, and extensively metabolized in all species tested.
Administration, Oral↗