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Biomedical subjects

T Iga

Publications and source records attributed to T Iga.

At least 217 records · Page 12Linked to original sources
PubMed1987

Tubulin as a major determinant of tissue distribution of vincristine.

The tissue distribution of vincristine was correlated with the tubulin content in different mouse tissues. The concentration of tubulin in the mouse tissues was determined by estimation of the tissue binding capacities for colchicine. Significant differences in the tubulin concentration were observed among the tissues. The comparison of the apparent tissue-to-plasma partition coefficients (KPapp) of vincristine (taken from the literature) with the tubulin concentration (expressed by the binding capacities for colchicine) showed a good correlation. These results suggest that the in vivo distribution of vincristine is predicted by the tissue tubulin concentration.

Animals↗
PubMed1987

Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple indicator dilution method.

Hepatic elimination of 4-methylumbelliferone (4-MU), which has been used as a model compound for conjugative metabolism, was studied by means of a multiple indicator dilution (MID) method in the isolated perfused rat liver. Using this method, three intrinsic hepatic clearances, CLint,inf, CLint,eff, and CLint,seq, which represent the influx, efflux, and sequestration processes, respectively, were obtained. When the dose was increased from a low dose (50 micrograms/rat liver) to a high dose (3000 micrograms/rat liver), the hepatic availability of 4-MU increased from 0.11 to 0.73. With increasing dose, the CLint,eff value increased approximately two times, while the CLint,seq value decreased to approximately one-third. The remarkable dose dependence of hepatic availability was due to nonlinearity in both CLint,eff and CLint,seq values. However, the CLint,inf value was almost independent of dose. The dose-dependent change in CLint,seq might be explained by the saturation of conjugative metabolism of 4-MU, while the increase in the CLint,eff value with increasing dose might be partly explained by the nonlinear tissue binding of 4-MU, since the tissue unbound fraction determined by an ultrafiltration method using liver homogenate increased approximately 1.5 times at higher concentration of 4-MU compared to that at lower concentrations. In addition, based on a comparison of the individual intrinsic clearances, i.e., CLint,inf, CLint,eff, and CLint,seq, the major determining process of the apparent hepatic intrinsic clearance of 4-MU is thought to be the sequestration process at the high dose. However, at the low dose, the membrane transport process (influx and efflux processes) as well as the sequestration process also determine the apparent hepatic intrinsic clearance.

Animals↗
PubMed1987

Effect of a diffusional barrier to a metabolite across hepatocytes on its kinetics in "enzyme-distributed" models: a computer-aided simulation study.

The effect of a diffusional barrier to a metabolite between the blood and hepatocytes on elimination kinetics of formed and preformed metabolites was predicted under various enzymic distributions in the liver by computer-aided simulation. Sequential metabolism by which the primary metabolite (MI) is generated from the parent drug (D) and further metabolized to the terminal metabolite (MII) by enzymes A and B, respectively, was chosen for the simulation. Moreover, four models of enzyme distribution patterns were defined with regard to the hepatic blood flow path. The extraction ratios for the preformed and formed metabolites (designated as Em and Ep----m, respectively) were simulated by varying both the average intrinsic clearance of enzyme B (CLint,B) and the permeability of hepatocytes for MI (Pm), while keeping the average intrinsic clearance of enzyme A (CLint,A) equal to hepatic blood flow (Q). When a rapid equilibrium of MI between the blood and hepatocytes held, i.e., Pm was large relative to Q, Em was equal to or higher than Ep----m for all models, as previously shown by Pang and Stillwell. By contrast, it was found that when a diffusional barrier for MI existed, i.e., Pm was small relative to Q, Em was equal to or lower than Ep----m. Furthermore, it was observed that the smaller Pm became, the larger the difference between Em and Ep----m became. We further simulated the effect of the intrinsic clearance (CLint,C) for a metabolic pathway, which competes for that by enzyme A, on the Ep----m value. In the model assuming even distribution of all the enzymes along the flow path, irrespective of the CLint,C value, a similar effect of Pm on Ep----m was observed when the Pm value was relatively small (Pm less than Q). By contrast, in the case of uneven enzymic distributions of enzymes A and B, the effect of the CLint,C value on the relationship between Pm and Ep----m occurred to some extent. From these simulations, it was concluded that lower membrane permeability (Pm) both diminishes the entry of preformed metabolite into the hepatocytes and accelerates the removal of intracellularly formed metabolite (through sequential metabolism) by diminishing its efflux, yielding lower Em than Ep----m. When Pm becomes small (Pm less than 1/10Q), these mechanisms for lower Em than Ep----m predominate over other mechanisms such as the presence of a competing metabolic route and uneven distribution of enzymes.

Biotransformation↗
PubMed1987

Tracer disposition kinetics in the determination of local cerebral blood flow by a venous equilibrium model, tube model, and distributed model.

Tracer distribution kinetics in the determination of local cerebral blood flow (LCBF) were examined by using three models, i.e., venous equilibrium, tube, and distributed models. The technique most commonly used for measuring LCBF is the tissue uptake method, which was first developed and applied by Kety (1951). The measurement of LCBF with the 14C-iodoantipyrine (IAP) method is calculated by using an equation derived by Kety based on the Fick's principle and a two-compartment model of blood-tissue exchange and tissue concentration at a single data point (Sakurada et al., 1978). The procedure, in which the tissue is to be in equilibrium with venous blood, will be referred to as the tissue equilibration model. In this article, effects of the concentration gradient of tracer along the length of the capillary (tube model) and the transverse heterogeneity in the capillary transit time (distributed model) on the determination of LCBF were theoretically analyzed for the tissue sampling method. Similarities and differences among these models are explored. The rank order of the LCBF calculated by using arterial blood concentration time courses and the tissue concentration of tracer based on each model were tube model (model II) less than distributed model (model III) less than venous equilibrium model (model I). Data on 14C-IAP kinetics reported by Ohno et al. (1979) were employed. The LCBFs calculated based on model I were 45-260% larger than those in models II or III. To discriminate among three models, we propose to examine the effect of altering the venous infusion time of tracer on the apparent tissue-to-blood concentration ratio (lambda app). A range of the ratio of the predicted lambda app in models II or III to that in model I was from 0.6 to 1.3. In the future, there may be a need to determine which model should be used to calculate the LCBF based on this discriminator and to develop another discriminator by using multiple data points based on positron emission tomography.

Animals↗
PubMed1987

Pharmacokinetic study of 4-methylumbelliferone in mice.

The pharmacokinetic behavior of 4-methylumbelliferone (4-MU), a compound known to be excreted as conjugated metabolites, was studied in mice and the results were compared with those reported in rats. Plasma half-life of the terminal phase (t1/2,beta) of mice after an intravenous administration of 4-MU was approximately one-twenty fifth of that of rats. Mice showed a dose dependency in both hepatic and extrahepatic clearances, though dose dependent hepatic clearance is reported to be the main route of elimination in rats. In the same dose range (10-25 mg/kg), the hepatic intrinsic clearance per unit body weight of mice was approximately 5 times larger than that of rats. The blood-to-plasma concentration ratio and the unbound volume of distribution of tissues of mice were smaller than those of rats. It was concluded that the shorter t1/2,beta of mice than that of rats may be due to the larger hepatic clearance, the presence of extrahepatic clearance and the smaller volume of distribution.

Animals↗
PubMed1987

Variation in D-glucose uptake along the intestinal tract.

The variation in D-glucose uptake along the intestinal tract was examined by dividing the entire rat small intestine into 10 segments of equal length and by using everted sacs. The superiority of jejunum to ileum in D-glucose uptake, which is generally accepted, was supported by this work. It was attributed mainly to the variation in the maximal transport velocity of the Michaelis-Menten type carrier-mediated transport system with a clear kinetic border in the distal location of the small intestine, between segments 7 and 8. Information obtained in this study is useful for understanding and estimating the absorption process, or the time-course of absorption, of D-glucose as it passes down in the intestinal tract.

Animals↗
PubMed1987

Clinical application of biofeedback treatment with a microvibration transducer.

This article demonstrates one clinical application of biofeedback treatment with a microvibration (MV) transducer to relieve functional tremors. A MV transducer, a kind of accelerometer, was originally developed to detect invisible tremors from the body surface but this equipment is also utilized to detect visible tremors to convert them to auditory signals. Our method uses almost the same procedure as electromyographic biofeedback treatment. The threshold level for production of auditory signals should be determined as high as possible between the superimposed amplitudes of essential MV and tremor components. As the sessions progress, the predeterminate threshold level should be gradually lowered to almost the same amplitude as MV itself. In determining the threshold, it is more appropriate to utilize records of the frequency band in which the tremor components are described more clearly, in order to remove noises or MV waves of different frequency ranges. Because of the high sensitivity of this accelerometer, such "tremor feedback" treatment can be recommended only if the tremor is present while the patient is resting or remains still.

Adult↗
PubMed1987

Transport of benzylpenicillin by the rat choroid plexus in vitro.

To characterize the transport system by which benzylpenicillin, an organic anion, is accumulated by the isolated rat choroid plexus, kinetic analysis of benzylpenicillin transport was performed. Accumulation of benzylpenicillin was against an electrochemical potential gradient via a saturable process (Km = 58 microM and Vmax = 84 nmol/ml of tissue per min) that was inhibited by sulfhydryl reagents (p-hydroxymercuribenzoate and N-ethylmaleimide), metabolic inhibitors (KCN and 2,4-dinitrophenol) and anion exchange inhibitors (4-acetamide-4'-isothiocyanatostilbene-2,2'-disulfonic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid), but is major transport system did not require the inward Na+ gradient. Organic anions, such as 5-hydroxyindoleacetic acid, homovanillic acid, p-aminohippuric acid and probenecid inhibited the accumulation of benzylpenicillin, whereas dipeptides did not affect it. Kinetic analysis of the accumulation of benzylpenicillin suggests that both phenoxymethylpenicillin and cefpiramide are also transported via the benzylpenicillin transport system. Other penicillin and cephalosporin derivatives inhibited the accumulation of benzylpenicillin with different affinities. Penicillin derivatives without dissociating groups in the side chain had the higher affinity for the benzylpenicillin transport system than other beta-lactam antibiotics did. Among penicillin derivatives examined, a good correlation (r = 0.92) was observed between the lipophilicity and the affinity for the benzylpenicillin transport system, whereas no correlation was observed among the cephalosporin derivatives. These findings suggest that the major transport system of benzylpenicillin in the rat choroid plexus is via a carrier-mediated active anion transport process which is distinct from that of dipeptides, and does not require the inward Na+ gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Anion exchanger mediates benzylpenicillin transport in rat choroid plexus.

Transport characteristics of benzylpenicillin in the central nervous system was examined using ATP-depleted rat choroid plexus. In the presence of an outwardly directed Cl- gradient, accumulation of benzylpenicillin was stimulated markedly compared with the accumulation in the absence of Cl- gradient. Under Cl- gradient conditions, benzylpenicillin was accumulated transiently at a concentration approximately 1.7-fold higher than at equilibrium ("overshoot") implying the uphill transport. The Cl- gradient-stimulated accumulation of benzylpenicillin was not solely due to the changes in the membrane potential or in the intracellular pH. Accumulation of benzylpenicillin in choroid plexuses preloaded with HCO3-, SCN- or benzylpenicillin also was stimulated compared with the accumulation in unpreloaded choroid plexuses. The Cl- gradient-stimulated benzylpenicillin accumulation was saturable (Km = 13.6 microM and Vmax = 3.76 nmol/ml of tissue per min), and was reduced by sulfhydryl reagents (p-hydroxymercuribenzoic acid, p-chloromercuribenzoic acid, p-chloromercuribenzenesulfonic acid and N-ethylmaleimide). Probenecid and anionic exchange inhibitors (furosemide, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid) inhibited the Cl- gradient-stimulated benzylpenicillin accumulation in a dose-dependent fashion. An inwardly directed Na+ gradient did not stimulate the accumulation of benzylpenicillin. These findings suggest that the principal mechanism for the uphill transport of benzylpenicillin in the rat choroid plexus is via an anionic exchanger.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1986

Na+-dependent p-aminohippurate transport at the basolateral side of the isolated perfused rat kidney.

The uptake of p-amino[3H]hippurate by isolated perfused rat kidney was studied to characterize the mechanism which was responsible for organic anion transport process. A rapid injection multiple indicator dilution technique and the distributed two-compartment model of Sawada et al. (Computer Methods Programs Biomed., 20 (1985) 51) were employed. Some characteristics of a carrier-mediated transport from the antiluminal space to the intracellular space for p-aminohippurate at the basolateral side were demonstrated: the uptake was stimulated by the countertransport effect and showed Na+ dependency. These findings are consistent with p-amino[3H]hippurate's being taken up into the isolated rat basolateral membrane vesicle by Na+-dependent carrier-mediated transport (J. Pharmacol. Exp. Ther. 227 (1983) 122). It is suggested that the multiple indicator dilution technique is a sensitive new method to study the mechanisms of renal tubular transport in the living kidney as an organ.

Aminohippuric Acids↗
PubMed1986

Determination of kinetic parameters of a carrier-mediated transport in the perfused intestine by two-dimensional laminar flow model: effects of the unstirred water layer.

The kinetic parameters of a carrier-mediated transport for D-glucose and for taurocholate were determined from rat in situ intestinal single perfusion experiments. The true parameters were obtained by the two-dimensional laminar flow model, in which the solute concentration at the aqueous-intestinal membrane interface can be calculated numerically without assuming the aqueous diffusion layer, discriminating the effects of the unstirred water layer. The true Michaelis constant was 4.5 mM for D-glucose and 1.5 mM for taurocholate. The true maximal transport velocity was 3.4 nmol/s per cm2 for D-glucose and 0.29 nmol/s per cm2 for taurocholate. The apparent Michaelis constant was raised by the factor of 6.6 for D-glucose and 3.6 for taurocholate due to the effects of the unstirred water layer. The maximal transport velocity was relatively unaffected by the unstirred water layer in both compounds. The values of the effective (operational) thickness of the unstirred water layer were compatible with those reported previously by employing various experimental methods. The kinetic parameters obtained in vitro everted sacs, for comparison, almost coincided with the true ones in situ. Therefore, the two-dimensional laminar flow model is shown to be valid not only for determining the kinetic parameters of a carrier-mediated transport in situ but also for predicting the absorption rate in situ from the uptake rate in vitro.

Animals↗
PubMed1986

Intestinal absorption by carrier-mediated transports: two-dimensional laminar flow model.

The two-dimensional laminar flow model was adapted to the intestinal absorption of drug and biological substances by carrier-mediated transports in the single perfusion experiments and we investigated the effects of the unstirred water layer on the Michaelis constant and the maximum transport velocity. According to the calculated values, the half saturation concentration at the inlet was larger than the true Michaelis constant at the intestinal wall. The apparent values of the Michaelis constant and the maximum transport velocity obtained by the Lineweaver-Burk plots were larger than the true ones, and the relations were not linear. These deviations increased as the ratio of the maximum transport velocity to the Michaelis constant increased and as the perfusion rate decreased. In the concurrent presence of a passive transport, underestimation of the carrier-mediated transport component of the absorption rate (at steady state) was predicted. It is considered to cause the underestimation of the maximum transport velocity. When water was absorbed (or secreted), the absorption rate increased (or decreased) and did not saturate. This two-dimensional laminar flow model would enable us to analyze the experimental data to determine the true values of the Michaelis constant and the maximum transport velocity.

Absorption↗
PubMed1986

Determination of the membrane permeability coefficient and the reflection coefficient by the two-dimensional laminar flow model for intestinal perfusion experiments.

We performed single perfusion experiments in the small intestine of rats in order to prove that the two-dimensional laminar flow model is suitable to determine the membrane permeability coefficient and the reflection coefficient. We used progesterone as an aqueous-diffusion-limited drug, urea as a membrane transport-limited drug and the tritiated water as an intermediate substance. The membrane permeability coefficient for progesterone was calculated to be 3.6 X 10(-4) cm/s. This value did not change when the thickness of the aqueous diffusion layer was altered by increasing the perfusion rate 10-fold. It was directly demonstrated that the two-dimensional laminar flow model was suitable to analyze the data of intestinal perfusion experiments. Membrane permeability coefficients for urea and tritiated water were determined to be 3.4 X 10(-5) cm/s and 8.9 X 10(-5) cm/s, respectively. In the presence of water absorption with the hypotonic perfusion solution, the reflection coefficient for urea was 0.84. This value is thought to be theoretically reasonable, suggesting the usefullness of the two-dimensional laminar flow model to obtain the reflection coefficient in the intestinal membrane.

Animals↗
PubMed1986

Local light stimulation of melanophores of a teleost, Zacco temmincki.

Responses of melanophores of the teleost, Zacco temmincki, to local light stimulation were examined in preparations of isolated scales. The melanophores induced the aggregation of melanosomes in darkness and their dispersion in light. Local illumination of a melanophore in the melanosome-dispersed state inhibited centripetal migration of melanosomes only in the stimulated area. Local illumination of a pigment-free branch of a melanophore with aggregated melanosomes generally brought about pigment dispersion into the stimulated area. However, when that area was at a significant distance from the edge of the central melanosome mass, the melanosomes never migrated into the irradiated area. Local illumination of the centrosphere of a cell inhibited the full aggregation of melanosomes in the dispersed and aggregated state. The degree of the inhibition depended on the size of the irradiated area. The results suggest that photoreceptive sites are distributed over the whole of a cell, and that the movements of melanosomes are regulated locally in a very precise manner.

Animals↗