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Y Sugiyama

Publications and source records attributed to Y Sugiyama.

At least 37 records · Page 2Linked to original sources
PubMed2001

Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier (Part 1).

Penetration through the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) is necessary if a drug is to achieve the required concentration for a desired pharmacological effect. Efflux transport systems at the BBB and BCSFB provide a protective barrier function by removing drugs from the brain or cerebrospinal fluid and transferring them to the systemic circulation, respectively; several transporters at the BBB and BCSFB have been identified. Efflux transport should be taken into consideration during drug development to improve brain penetration and to avoid drug-drug interactions involving these transporters and subsequent side effects.

Journal Article↗
PubMed2001

Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier (Part 2).

Penetration of the blood-brain barrier or blood-cerebrospinal fluid barrier is necessary if a drug is to achieve the required concentration for a desired pharmacological effect. Efflux transport systems at such barriers provide protection for the CNS by removing drugs from the brain or cerebrospinal fluid, and transferring them to the systemic circulation. In Part 2 of this review, in vivo and in vitro studies of efflux transport via these barriers are discussed, with reference to the transporters previously described in Part 1(1).

Journal Article↗
PubMed2001

Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1.

Ectopic expression of Jab1/CSN5 induces specific down-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27 (p27(Kip1)) in a manner dependent upon transportation from the nucleus to the cytoplasm. Here we show that Grb2 and Grb3-3, the molecules functioning as an adaptor in the signal transduction pathway, specifically and directly bind to p27 in the cytoplasm and participate in the regulation of p27. The interaction requires the C-terminal SH3-domain of Grb2/3-3 and the proline-rich sequence contained in p27 immediately downstream of the Cdk binding domain. In living cells, enforcement of the cytoplasmic localization of p27, either by artificial manipulation of the nuclear/cytoplasmic transport signal sequence or by coexpression of ectopic Jab1/CSN5, markedly enhances the stable interaction between p27 and Grb2. Overexpression of Grb2 accelerates Jab1/CSN5-mediated degradation of p27, while Grb3-3 expression suppresses it. A p27 mutant unable to bind to Grb2 is transported into the cytoplasm in cells ectopically expressing Jab1/CSN5 but is refractory to the subsequent degradation. These findings indicate that Grb2 participates in a negative regulation of p27 and may directly link the signal transduction pathway with the cell cycle regulatory machinery.

3T3 Cells↗
PubMed2001

Investigation of 5-FU disposition after oral administration of capecitabine, a triple-prodrug of 5-FU, using a physiologically based pharmacokinetic model in a human cancer xenograft model: comparison of the simulated 5-FU exposures in the tumour tissue between human and xenograft model.

The nonlinear pharmacokinetics of capecitabine, a triple prodrug of 5-FU preferentially activated in tumour tissues, was investigated in human cancer xenograft models. A physiologically based pharmacokinetic (PBPK) model integrating the activation process of capecitabine to 5-FU and 5-FU elimination was constructed to describe the concentration/time profiles of capecitabine and its three metabolites, including 5-FU, in blood and organs. All the biochemical parameters (enzyme kinetic parameters, plasma protein binding and tissue binding of capecitabine and its metabolites) integrated in this model were measured in vitro. The simulated curves for the blood and tumour concentrations of capecitabine and its metabolites can basically describe the observed values. A simple prodrug of 5-FU, doxifluridine, is known to be activated to 5-FU to some extent in the gastrointestinal (GI) tract, causing diarrhoea, which is the dose limiting side effect of doxifluridine. Consequently, the therapeutic index (the ratio of 5-FU AUC in the tumour to that in GI) after the administration of effective dose capecitabine was predicted by this PBPK model and found to be five times and 3000 times greater than that of doxifluridine and 5-FU, respectively. This was compatible with the previous result for the difference in the ratio of the toxic dose to the minimum effective dose between capecitabine and doxifluridine, suggesting that 5-FU preferentially accumulates in tumour tissue after oral administration of capecitabine compared with the other drugs (doxifluridine and 5-FU). The 5-FU AUC in tumour tissue of human cancer xenograft models at the minimum effective dose was comparable with those estimated for humans at the clinical dose. In addition, the predicted therapeutic indices at the respective doses were correlated well between humans and mice (xenograft model). These results suggest that the 5-FU AUC in human tumour tissue at its clinically effective dose can be predicted based on the PBPK model inasmuch as the 5-FU AUC in a human cancer xenograft model at its effective dose may be measured or simulated.

Administration, Oral↗
PubMed2001

In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans.

We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CL(int)) for 4-hydroxylation and CYP3A4 content and between the CL(int) for alpha-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CL(int) for CYP3A4 was about 2-fold higher than the CL(int) for CYP3A5 in the case of 4-hydroxylation. However, the CL(int) for CYP3A5 was about 3-fold higher than the CL(int) for CYP3A4 in the case of alpha-hydroxylation. The metabolic rates for 4- and alpha-hydroxylation increased as the added amount of cytochrome b(5) increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b(5). The values of CL(int), in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CL(int) value (sum of 4- and alpha-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitro K(i) values and reported pharmacokinetic parameters of ketoconazole was 2.30-2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73-1.79 vs 1.58-1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants.

Adult↗
PubMed2001

Activation of rho is involved in the mechanism of hydrogen-peroxide-induced lung edema in isolated perfused rabbit lung.

Acute lung injury is attributed primarily to increased vascular permeability caused by reactive oxygen species derived from neutrophils, such as hydrogen peroxide (H2O2). Increased permeability is accompanied by the contraction and cytoskeleton reorganization of endothelial cells, resulting in intercellular gap formation. The Rho family of Ras-like GTPases is implicated in the regulation of the cytoskeleton and cell contraction. We examined the role of Rho in H2O2-induced pulmonary edema with the use of isolated perfused rabbit lungs. To our knowledge, this is the first study to examine the role of Rho in increased vascular permeability induced by H2O2 in perfused lungs. Vascular permeability was evaluated on the basis of the capillary filtration coefficient (Kfc, ml/min/cm H2O/100 g). We found that H2O2 (300 microM) increased lung weight, Kfc, and pulmonary capillary pressure. These effects of H2O2 were abolished by treatment with Y-27632 (50 microM), an inhibitor of the Rho effector p160 ROCK. In contrast, the muscular relaxant papaverine inhibited the H2O2-induced rise in pulmonary capillary pressure, but did not suppress the increases in lung weight and Kfc. These findings indicate that H2O2 causes pulmonary edema by elevating hydrostatic pressure and increasing vascular permeability. Y-27632 inhibited the formation of pulmonary edema by blocking both of these H2O2-induced effects. Our results suggest that Rho-related pathways have a part in the mechanism of H2O2-induced pulmonary edema.

Amides↗
PubMed2001

Pneumatosis intestinalis in the small bowel of an adult: report of a case.

We present the case of a 70-year-old man found to have pneumatosis of the small intestine. An abdominal computed tomography (CT) scan detected massive intramural air in the entire circumference of the small intestine without any venous gas. During emergency surgery, 80 cm of the small bowel was removed. The pathological findings of thrombi in the resected specimen thus indicated that surgical intervention should be immediately performed in patients with pneumatosis throughout the small intestine. CT was useful for confirming the presence of intramural gas in pneumatosis of the small intestine. The presence of a massive amount of intramural gas in the entire small intestine circumference on the CT findings is thus considered to be an early indication of bowel infarction.

Aged↗
PubMed2001

Music therapy for children with Rett syndrome.

The Rett syndrome is good reactivity for sound and music. We enforced active music therapy (MT) individual session to patients with Rett syndrome. The patients were 4, 5 and 6-year-old. The active music therapy and individual session of 30 min/week were performed. It was recorded in video and description, and using the original evaluation list, six items of fact. On largest problem that is hand operation with purpose in childhood of Rett syndrome, we recorded the longest duration and frequency of hand grasping time in one session. There was the improvement of 35.0% of listening music, 33.3% play music, 13.3% singing music, 11.7% minute motion, 11.7% language, and 20.0% personal relation and sociality. The longest duration of hand grasping time was improved from 2 to 12 s in case 2 and from 7 to 80 s in case 3. Grasp frequency which showed the volition rapidly increased from 3 to 41 times, though the elongation for the duration of grasping was little for case 2. Rett syndrome is the disease in which the psychomotor performance regresses with the age, but the aspect that surely developed in the session could be evaluated. Rett syndrome has the ability understanding the music, and music therapy is suitable for them.

Child↗
PubMed2001

On-site diagnosis of H. pylori infection by urine.

We have recently developed an on-site diagnostic kit for H. pylori infection using urine (utilizing immunochromatographic method employing a nitrocellulose membrane coated by extracted H. pylori antigen). Accordingly, we investigated its usefulness in 155 consecutive dyspeptic patients using the 13C urea breath test as a gold standard and further compared its performance with two commercially available rapid diagnostic kits that use whole blood (Helisal Rapid Blood, and ImmunoCard H. pylori). As the results, the urine based on-site diagnostic kit provided 95.9% sensitivity and 87.9% specificity with 92.9% accuracy, which were comparable or even better than that of both rapid whole blood tests, suggesting its usefulness in screening of H. pylori infection.

Antigens, Bacterial↗
PubMed2001

Cisplatin-loaded polymer-metal complex micelle with time-modulated decaying property as a novel drug delivery system.

PURPOSE: The pharmacological activity and pharmacokinetics of cisplatin (CDDP)-loaded polymeric micelles were examined to reveal their usefulness as a novel tumor-directed drug carrier system of CDDP. METHODS: In biodistribution assay, free CDDP or CDDP-loaded micelles were administered intravenously to Lewis lung carcinoma-bearing mice. Antitumor activity and nephrotoxicity were respectively evaluated by the measurement of tumor size and plasma blood urea nitrogen (BUN) after single bolus i.v. administration of each drug. RESULTS: The time profile of the plasma Pt level after the injection of the micelles exhibited a time-modulated disappearance as observed in saline in vitro. The micelles exhibited 5.2- and 4.6-fold higher AUC of Pt in the plasma and tumor, respectively, with minimal change in the kidney, in comparison with free CDDP, suggesting that prolonged circulation of Pt in circulation and specific accumulation in the tumor were achieved utilizing the micellar drug carrier system. Administration of the micelles at the dose exhibiting antitumor activity similar to free CDDP did not increase the plasma BUN, whereas free CDDP induced its remarkable increase. CONCLUSION: CDDP-loaded micelles restrained nephrotoxicity, which is the dose-limiting factor of CDDP, while exhibiting tumor-specific accumulation. Thus, CDDP-loaded micelles are expected to be a novel formulation of CDDP for clinical use.

Animals↗
PubMed2001

Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver.

PURPOSE: It has been shown that plasma concentration and urinary excretion of bile acids is elevated under the cholestatic/ hyperbilirubinemic conditions. Previously, it was demonstrated that the plasma concentration of bile acids was elevated in the multidrug resistance-associated protein 2 (Mrp2)-deficient rats. The purpose of the present study was to compare the sinusoidal efflux clearance of taurocholate (TC) between Mrp2-deficient Eisai hyperbilirubinemic rats (EHBR) and normal rats. METHOD: Hepatic disposition of the [3H]TC was examined in the perfused liver. Apparent efflux clearance (PSnet, eff) of [3H]TC from hepatocytes to outflow across the sinusoidal membrane was defined as the amount of [3H]TC excreted into the outflow from the liver divided by hepatic AUC of [3H]TC. Additionally, influx clearance (PSinf) was also determined by multiple indicator dilution method because PSnet, eff is also affected by PSinf. RESULTS: PSnet, eff was significantly higher in EHBR than that in Sprague-Dawley (SD) rats (16.6 +/- 1.7 vs. 6.1 +/- 1.3 microL/min/g liver, P < 0.01). In contrast, PSinf was comparable between SD rats and EHBR. Kinetic analysis suggested that the intrinsic clearance for the efflux of [3H]TC across the sinusoidal membrane in EHBR was higher than that in SD rats (10.4 +/- 1.0 v.s. 23.3 +/- 1.7 microL/min/g liver, P < 0.01). CONCLUSIONS: Enhanced sinusoidal efflux of TC in EHBR may be related to the altered disposition of bile acids in the mutant rats. Because Mrp3 transports TC and its expression is induced on the basolateral membrane of Mrp2-deficient rats, the enhanced sinusoidal efflux of TC in EHBR may be accounted for, at least partially, by the increased expression of Mrp3.

Animals↗
PubMed2001

A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans: the mechanism for tumor-selective accumulation of 5-FU.

PURPOSE: To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. METHOD: The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations. RESULTS: The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges. CONCLUSIONS: It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.

Antimetabolites, Antineoplastic↗
PubMed2001

Kinetic analysis of the disposition of insulin-like growth factor 1 in healthy volunteers.

PURPOSE: Insulin-like growth factor 1 (IGF-1) is predominantly bound to its specific binding proteins (IGFBPs) in circulating plasma. In the present study, pharmacokinetic analysis of IGF-1 was performed in healthy volunteers to characterize the effect of interactions with IGFBPs on IGF-1 disposition. METHODS: Plasma concentration profiles of both free and bound IGF-1 were examined at several doses. An in vitro plasma protein binding was also analyzed. RESULTS: The total body clearance (CLtotal) for the free IGF-1 was much higher than the creatinine clearance, suggesting that the major elimination pathway is by a route other than renal glomerular filtration. The CLtotal for the free IGF-1 exhibited a dose-dependent reduction whereas that for the sum of unbound and bound IGF-1 increased on increasing the dose. The data obtained fitted closely a one-compartment model that involved the binding and dissociation of IGF-1, as well as its biosynthesis and elimination. The estimated parameters suggest that IGF-1 exhibits high affinity binding to IGFBPs. the rate-limiting step in the overall elimination being the dissociation from IGFBPs. CONCLUSIONS: The saturation of both the plasma protein binding and elimination accounts for the nonlinear pharmacokinetic profile. The binding to IGFBPs markedly limits both the distribution and elimination of IGF-1.

Adult↗
PubMed2001

Up-regulation of carnitine transporters helps maintain tissue carnitine levels in carnitine deficiency induced by pivalic acid.

PURPOSE: Pivalic acid (PVA) forms conjugates with endogenous carnitine and enhances its excretion. The purpose of this study is to determine whether tissue carnitine levels decrease in parallel with plasma levels in carnitine deficiency induced by PVA. METHODS: PVA was orally administered to rats for 5 days. Carnitine levels in plasma, liver, kidney, muscle, and heart were monitored. The tissue uptake clearance (CLuptake) was determined in vivo by the integration plot method. Hepatocytes were prepared from control and PVA-treated rats, and the uptake of L-carnitine was determined. RESULTS: Plasma concentrations of L-carnitine decreased as a result of the enhanced carnitine elimination as pivaloylcarnitine (PCN) when rats were treated with PVA. However, L-carnitine concentrations in liver, muscle, and heart remained relatively constant during the study. period. CLuptake increased in liver and muscle and, thus, the rate of carnitine uptake from plasma into these tissues did not change even at low plasma concentrations. This helps maintain carnitine levels in these tissues. Up-regulation of carnitine transporters is suggested to be a mechanism for the increased CLuptake. CONCLUSIONS: In the carnitine deficiency state induced by PVA, increased CLuptake owing to up-regulation of carnitine transporters is suggested to help maintain carnitine levels in some tissues.

Animals↗
PubMed2001

Physicochemical parameters responsible for the affinity of methotrexate analogs for rat canalicular multispecific organic anion transporter (cMOAT/MRP2).

PURPOSE: Canalicular multispecific organic anion transporter (cMOAT/MRP2) is known to exhibit a broad substrate specificity toward amphiphatic organic anions, including methotrexate (MTX). The present study aims to identify the physicochemical properties of MTX derivatives that correlate with recognition specificity by cMOAT/MRP2. METHODS: We examined the inhibitory effect of MTX and 24 analogs on the transport of [3H]-S-(2,4-dinitrophenyl)glutathione by cMOAT/MRP2. The affinity constants of these compounds were compared with their physicochemical parameters. The primary active transport of several compounds was also confirmed. RESULTS: The affinity constants closely correlated with the octanol/water partition coefficient (clogP), and a linear combination of polar and nonpolar surface areas. The affinity for cMOAT/MRP2 also closely correlated with the molecular weight, which also showed a significant correlation with nonpolar surface area and clogP. CONCLUSIONS: Recognition by cMOAT/MRP2 depends on a balance of dynamic surface properties between the polar and nonpolar regions of MTX analogs. The so-called "molecular weight threshold" for the cMOAT/MRP2 affinity of these compounds can be explained by their physicochemical parameters, especially their nonpolar surface areas.

Adenosine Triphosphate↗
PubMed2001

Inhibition of in vitro metabolism of simvastatin by itraconazole in humans and prediction of in vivo drug-drug interactions.

PURPOSE: To evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans. METHODS: The inhibitory effect of itraconazole on simvastatin metabolism was evaluated using human liver microsomes and the Ki values were calculated for the unbound drug in the reaction mixture. A physiologically-based pharmacokinetic model was used to predict the maximum in vivo drug-drug interaction. RESULTS: Itraconazole competitively inhibited the metabolism of simvastatin to M-1 and M-2 with Ki values in the nM range. The area under the curve (AUC) of simvastatin after concomitant dosing with itraconazole was predicted to increase ca. 84-101-fold compared with that without administration of itraconazole. Taking into consideration the fact that this method predicts the maximum interaction, this agrees well with the clinical observation of a 19-fold increase. A similar prediction, based on the Ki value without taking into account the drug adsorption to microsomes, led to an underevaluation of the interaction. CONCLUSIONS: It was demonstrated that the competitive inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole is the main cause of the drug interaction and that a Ki value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions.

Anticholesteremic Agents↗
PubMed2001

Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein.

PURPOSE: MDR1 P-glycoprotein (P-gp) plays an important role in determining drug disposition. The purpose of the present study was to establish in vitro models to predict the in vivo function of P-gp. METHODS: As an in vitro method, the transcellular transport of 12 compounds across the monolayer of Caco-2- and MDR1-transfected cells was examined. The ability of these compounds to stimulate the ATP hydrolysis was also determined using the isolated membrane fraction expressing P-gp. As a parameter to describe the in vivo P-gp function, we calculated the brain-to-plasma concentration ratio of compounds in mdr1a/1b knockout mice divided by the same ratio in wild type mice. RESULTS: A good correlation was observed between the in vitro flux ratio across the monolayer and in vivo P-gp function for 12 compounds. Although all compounds that stimulated ATP hydrolysis were significantly transported by P-gp, some compounds were transported by P-gp without significantly affecting ATP hydrolysis. CONCLUSION: Collectively, the in vitro flux ratio across monolayers of P-gp-expressing cells may be used to predict in vivo P-gp function. The extent of ATP-hydrolysis in vitro may also be a useful parameter for in vivo prediction, particularly for eliminating P-gp substrates in high-throughput screening procedures.

ATP Binding Cassette Transporter, Subfamily B, Mem↗