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Biomedical subjects

I Tamai

Publications and source records attributed to I Tamai.

At least 127 records · Page 7Linked to original sources
PubMed1988

Kinetics of peritoneal drug transport in rats: an application of the pore theory of transcapillary exchange.

In order to quantitatively describe the peritoneal transport of drugs, this paper proposes a kinetic model that is based on the hydrodynamic pore theory of transcapillary exchange, and incorporates an explicit description of volume and osmolality changes in the dialysate. Sulfisoxazole (SIX) and benzoic acid (BA) were used as model compounds. Following intraperitoneal administration of dialysate in rats, the osmolality, volume, and drug concentration in the dialysate were measured with respect to time. The obtained data were analyzed to give hydrodynamic parameters for solvent and a solute (including drug) by a computer-aided curve-fitting procedure according to the differential equations derived from the model. The present method, requiring no approximation of the changes in dialysate volume, made it possible to predict the concentration profiles of BA under different initial conditions of dialysate (i.e., different osmolality and volume). Solvent drag effect contributed little to the peritoneal transport of SIX and slightly to that of BA. It was also found that the peritoneal transport of BA is blood-flow limited while that of SIX is diffusion limited.

Animals↗
PubMed1988

Peritoneal transport of beta-lactam antibiotics: effects of plasma protein binding and the interspecies relationship.

In order to examine quantitatively the effect of plasma protein binding on the peritoneal transport of beta-lactam antibiotics, we employed a kinetic model based on the pore theory of transcapillary exchange. This model incorporates the changes in the volume, osmolality, and antibiotic concentration in the dialysate, so that the apparent capillary membrane permeability (Pd) and the reflection coefficient (sigma d) of an antibiotic could be assessed. Six cephalosporins (cefatrizine, cefazolin, cefpiramide, ceftazidime, ceftriaxone, cephaloridine) were used as model compounds. While the unbound fractions of these antibiotics ranged widely from 0.08 to 0.57, including linear and nonlinear protein binding, the concentration-time profiles in plasma and the peritoneal dialysate after intravenous administration in rats could be interpreted well by our model, assuming that only the unbound antibiotic is available for the peritoneal transport. The estimated Pd values were almost the same among the drugs examined. Moreover, the Pd values of cefazolin in mice, rats, and rabbits exhibited a 0.83-power dependency on the animal body weight, indicating that Pd is significantly related to the peritoneal surface area. On the other hand, the sigma d values of cefazolin were found to be almost the same among the animal species examined. Finally, the concentration-time profile of cefazolin in the dialysate after intravenous administration in a patient with end-stage renal failure was successfully predicted using the Pd value extrapolated from those of the experimental animals.

Aged↗
PubMed1988

Stereospecific absorption and degradation of cephalexin.

Stereospecific absorption and degradation of two stereoisomers about the alpha-amino group at the 7-position of cephalexin (CEX) have been investigated in the rat intestine. The L-isomer (L-CEX) was not found to be present either in serum or urine after oral administration, but the D-isomer (D-CEX) was well absorbed. In contrast to the saturable uptake of D-CEX (Kt = 10.54 +/- 1.73 mM, pH = 6.0) by the in-vitro everted intestinal sac, no appreciable uptake of L-CEX was observed. However, L-CEX competitively inhibited the uptake of D-CEX by the in-vitro everted intestine and the inhibitory constant (Ki) of L-CEX was determined to be 0.67 +/- 0.09 mM. L-CEX was rapidly degraded in-vitro in the intestinal tissue homogenate, serum and urine, while there was no appreciable degradation of D-CEX. Analysis of the major metabolite of L-CEX by high-performance liquid chromatography identified it as 7-aminodeacetoxycephalosporanic acid (7-ADCA). Furthermore, 7-ADCA was detected in serum after oral administration of L-CEX, indicating significant absorption of L-CEX as well as D-CEX. The results obtained suggest that both L- and D-CEX can be absorbed through the intestinal brush-border membrane via the same mechanism, most likely through the dipeptide transport system, and that the affinity of L-CEX to the carrier system is higher than that of D-CEX.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Inhibitory effects of quinolone antibacterial agents on gamma-aminobutyric acid binding to receptor sites in rat brain membranes.

The specific binding of 3H-labeled gamma-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3H]muscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, NY-198 [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [3H]muscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.

Animals↗
PubMed1988

Intraocular penetration kinetics of prednisolone after subconjunctival injection in rabbits.

Prednisolone concentrations in cornea, aqueous humor, and vitreous humor and the residual amount in conjunctival tissue were assayed by high-performance liquid chromatography during a 14-hour period after subconjunctival injection of prednisolone sodium succinate in rabbits. Prednisolone was concentrated in the corneal epithelium and reached a peak within 5 min, whereas the peak level of prednisolone in stroma-endothelium was achieved 1 h after the injection. There was an apparent linear binding of prednisolone with the ocular tissue homogenates and fluids except for the vitreous humor. However, the protein binding of prednisolone with vitreous humor showed marked concentration dependency. A pharmacokinetic model involving a rapid conversion to prednisolone from its ester prodrug, first-order transfer to various tissues, and first-order elimination of unbound prednisolone from vitreous humor succeeded in predicting the observed concentration-time profiles of prednisolone in various ocular tissues and fluids after subconjunctival injection at three different doses: 0.1, 1.0, and 10.0 mg/kg. The present model predicted that absorption into precorneal area and epithelium and direct penetration into aqueous humor and vitreous humor are 1.7, 0.1, and 0.2% of the applied dose, respectively, and that almost the entire dose (98%) is absorbed into the systemic circulation, with a half-life of 38 min.

Animals↗
PubMed1988

Carrier-mediated transport of cefixime, a new cephalosporin antibiotic, via an organic anion transport system in the rat renal brush-border membrane.

The renal excretion mechanism of cefixime, a newly developed and p.o. effective cephalosporin antibiotic, was investigated by using the renal brush-border membrane vesicles from the rat kidney cortex. The initial uptake rate of cefixime into an osmotically sensitive vesicular space showed concentration and temperature dependencies, indicating the presence of a carrier-mediated transport mechanism for cefixime. Kinetic parameters for apparently saturable and nonsaturable components were evaluated as follows: maximum uptake rate was 7.32 +/- 1.07 nmol/30 sec/mg of protein; Michaelis constant was 7.35 +/- 2.04 mM; and the first-order rate constant was 0.34 +/- 0.02 nmol/30 sec/mg of protein per mM. The uptake was not affected by an inward-directed gradient of Na+, K+, Li+, Rb+ or H+. In contrast, the initial uptake rate was enhanced by an inside-positive membrane potential imposed by valinomycin. Although amino acids, dipeptides and organic cations had no effects on the uptake of cefixime, organic anions such as probenecid and p-aminohippuric acid and anion transport inhibitors such as 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid and furosemide reduced the uptake significantly. Twenty beta-lactam antibiotics including both zwitter-ionic and anionic derivatives inhibited significantly the uptake of cefixime. Furthermore, by adding probenecid in the extravesicular medium, an efflux of cefixime from the brush-border membrane vesicles was enhanced significantly at the initial stage. Benzylpenicillin, cephalothin and cephradine also enhanced an efflux of cefixime to the same extent as observed by the addition of probenecid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Saturable uptake of cefixime, a new oral cephalosporin without an alpha-amino group, by the rat intestine.

The mechanism of intestinal uptake of cefixime, a new oral cephalosporin antibiotic, has been examined using the everted jejunum of rats. The initial uptake rates were apparently pH-dependent with the maximum rate at pH 5.0 and a 3-fold reduction at pH 7.0. The uptake at pH 5.0 followed mixed-type kinetics involving saturable and non-saturable processes in a manner similar to that for several amino-beta-lactam antibiotics. Cefixime uptake was inhibited significantly by 20 mM permeants such as cyclacillin, cephradine, benzylpenicillin, propicillin, glycyl-L-proline and glycyl-glycine. Replacement of Na+ in the medium with choline produced a slight but significant inhibition of cefixime uptake. In spite of the absence of significant inhibition by the amino acids glycine and proline, the dipeptide, glycyl-L-proline in Na+-free medium showed a marked inhibitory effect. The inhibition kinetics of cefixime uptake by glycyl-L-proline and cyclacillin were consistent with competitive-type inhibition. This study provides the first evidence of saturable intestinal uptake of a cephem antibiotic without an alpha-amino group in the side chain, suggesting transport through the dipeptide carrier system(s).

Animals↗
PubMed1987

Hydrolysis of prednisolone succinate by esterase in rabbit ocular tissue.

Prednisolone concentrations in serum after both subconjunctival and intravenous injections of prednisolone sodium succinate at a 1 mg/kg equivalent dose of prednisolone in rabbits were analyzed by regularly phased high-performance liquid chromatography. The systemic availability after subconjunctival injection was determined to be almost 1.0 by comparing areas under the serum concentration-time curves for both administration routes. The initial hydrolytic rate of prednisolone succinate ester was dependent on the amount of total protein in ocular tissue homogenates and fluids as well as that in serum. The rate followed Michaelis-Menten kinetics, with an almost consistent Michaelis constant. Although the maximum hydrolytic rate per unit amount of tissue protein was the highest in conjunctival tissue, followed by corneal tissue and serum, the esterase activity corrected by total protein in the whole rabbit body should be the highest in serum, followed by conjunctival tissue. These results indicate that prednisolone sodium succinate administered subconjunctivally is hydrolyzed rapidly by esterase and absorbed almost completely into the systemic circulation.

Animals↗
PubMed1987

Transport mechanism of cephalexin in isolated hepatocytes.

By using isolated rat hepatocytes, the mechanism of uptake of a zwitterionic beta-lactam antibiotic, cephalexin, was clarified. The uptake followed the combination of saturable carrier-mediated and nonsaturable first-order rate processes. The kinetic parameters were estimated as follows (mean +/- SD): maximum uptake rate (Vmax), 2.28 +/- 0.24 nmol/min/mg of protein; Michaelis constant (Kt), 6.28 +/- 0.31 mM and first-order rate constant (kd), 0.11 +/- 0.012 nmol/min/mg of protein/mM. There was no inhibitory effect by amino acids, dipeptides or organic cations, whereas an organic anion, probenecid, markedly inhibited the hepatic uptake of cephalexin. Several beta-lactam antibiotics including zwitterionic and anionic derivatives inhibited cephalexin uptake significantly. The inhibition kinetics revealed that benzylpenicillin and the stereo-isomer l-cephalexin competitively inhibited cephalexin uptake. Furthermore, the efflux of cephalexin from the cells was stimulated by adding benzylpenicillin in the extracellular medium. These results demonstrated that all beta-lactam antibiotics have a common transport system with an organic anion such as probenecid, irrespective of their ionic charges, though a cationic charge on the molecule is less advantageous for being recognized by the carrier system.

Amino Acids↗
PubMed1987

Kinetics of benzylpenicillin metabolism in isolated rat hepatocytes.

The metabolism of benzylpenicillin (PCG) in isolated rat hepatocytes was investigated. The evidence of metabolizing activity for PCG in hepatic cells was obtained as follows; the disappearance rate of PCG from the incubation medium followed Michaelis-Menten kinetics and was dependent on the cellular protein concentration, while PCG did not disappear when it was incubated with cells denaturated by heat. The rate of disappearance of PCG was reduced significantly in the presence of the structural analogue of PCG such as phenoxymethylpenicillin in the incubation medium. The major metabolite of PCG was identified, by high performance liquid chromatographic analysis, to be penicilloic acid (PA) of PCG. A kinetic model describing the intra- and extra-cellular concentrations of PCG and PA was developed. The proposed model fitted well the time course of changes in the concentration of PCG and PA. The clearance of the uptake of PCG by isolated hepatocytes was evaluated to be about 23-times greater than that of metabolism of PCG.

Animals↗
PubMed1987

H+ gradient-dependent and carrier-mediated transport of cefixime, a new cephalosporin antibiotic, across brush-border membrane vesicles from rat small intestine.

The characteristics of the transport of cefixime, a new p.o. cephalosporin, antibiotic, were studied by using brush-border membrane vesicles from the rat small intestine. The initial rate of uptake of cefixime was not affected by the presence of an inward gradient of either Na+ or other monovalent cations. With an intravesicular pHi of 7.5, optimal cefixime uptake occurred at an extravesicular pHo of 5.0, with about 6-fold acceleration compared with that in the absence of an inward proton gradient (pHi = pHo = 7.5). A protonophore, carbonyl-cyanide-4-trifluoromethoxy-phenylhydrazone, abolished the stimulating effect of low pHo. In the presence of a sufficient inward proton gradient (pHi = 7.5, pHo = 5.0), cefixime uptake showed an overshoot phenomenon and apparent saturation kinetics expressed by the Michaelis-Menten equation with the maximum rate of 2.67 +/- 0.06 nmol/30 sec/mg of protein and a Michaelis constant of 0.83 +/- 0.04 mM. Cefixime uptake was inhibited competitively by glycyl-L-proline and stimulated by the countertransport effect of this dipeptide. The other peptides also inhibited cefixime uptake significantly. A valinomycin-induced inside-negative K+-diffusion potential had a dramatic reducing effect on the uptake of dianionic cefixime. All the data obtained in this study demonstrate that cefixime transport across the brush-border membrane vesicles is carrier-mediated, independent of Na+ and dependent on a H+ gradient via the peptide transport systems.

Amino Acids↗
PubMed1986

Uptake of benzylpenicillin, cefpiramide and cefazolin by freshly prepared rat hepatocytes. Evidence for a carrier-mediated transport system.

The kinetics and mechanism of the hepatic uptake of beta-lactam antibiotics were studied by using freshly prepared rat hepatocytes. The initial uptake rates of benzylpenicillin and cefpiramide represented both saturable and nonsaturable transport processes, whereas that of cefazolin showed an apparently nonsaturable uptake process within the concentration range below 4 mM. The apparent nonsaturable uptake rate constants for benzylpenicillin, cefpiramide and cefazolin were 0.580, 0.047 and 0.289 nmoles/min/mg protein/mM respectively. The apparent values of Kt and Vmax describing the saturable transport were 0.473 +/- 0.158 mM and 2.02 +/- 0.48 nmoles/min/mg protein for benzylpenicillin and 0.847 +/- 0.254 mM and 0.70 +/- 0.18 nmoles/min/mg protein for cefpiramide respectively. The Arrhenius plot of benzylpenicillin uptake of 200 microM presented a single straight line in the range of 22 degrees-37 degrees with an activation energy of 16.8 kcal/mole. An energy requirement was also demonstrated for benzylpenicillin uptake as metabolic inhibitors (antimycin A, NaCN, rotenone and 2,4-dinitrophenol) significantly reduced the initial uptake rate of benzylpenicillin (P less than 0.05). Uptake of benzylpenicillin (200 microM) was not inhibited by ouabain (1 mM). Benzylpenicillin uptake was inhibited competitively by phenoxymethylpenicillin, cefpiramide and cefazolin with the inhibition constants, Ki, of 0.680, 0.583 and 11.7 mM respectively. Benzylpenicillin also inhibited competitively the uptake of cefpiramide with a Ki of 0.655 mM. From these results it was considered that a carrier-mediated uptake system participates in the hepatic uptake of at least four of the beta-lactam antibiotics examined in this study.

Animals↗
PubMed1986

Kinetic evidence for a common transport route of benzylpenicillin and probenecid by freshly prepared hepatocytes in rats. Influence of sodium ion, organic anions, amino acids and peptides on benzylpenicillin uptake.

Hepatic transport system of benzylpenicillin was characterized by using freshly prepared rat hepatocytes. Uptake of benzylpenicillin and cefpiramide did not require the presence of sodium ion in the incubation medium. No influence of several kinds of amino acids (leucine, histidine, phenylalanine, valine, alanine, glutamic acid and glycine) and peptides (prolyl-leucine, glycyl-glycine, glycyl-sarcosine, glycyl-leucine and gamma-glutamyl-cysteinylglycine) was observed for benzylpenicillin uptake into hepatocytes. Taurocholic acid and cholic acid significantly inhibited benzylpenicillin uptake. The kinetic study revealed that taurocholic acid inhibited benzylpenicillin uptake in a noncompetitive fashion. A similar effect of benzylpenicillin on taurocholic acid uptake was observed, suggesting that the affinity site of the hepatic transport carrier of benzylpenicillin is distinct from that of taurocholic acid. It is noteworthy that p-aminohippuric acid and p-acetylaminohippuric acid did not inhibit benzylpenicillin uptake. In contrast to the mutual inhibition behavior of benzylpenicillin and taurocholic acid, benzylpenicillin is fully and competitively inhibited by the simultaneous addition of probenecid. The inhibition constant Ki value of probenecid was calculated to be 0.322 mM. The uptake of probenecid was also significantly inhibited by benzylpenicillin. It is postulated that the affinity site of benzylpenicillin transport carrier is the same as that of probenecid and that the whole process of the benzylpenicillin transport system is common, at least in part, to the probenecid transport process in the liver.

Amino Acids↗
PubMed1986

Evidence for a carrier-mediated transport system in the small intestine available for FK089, a new cephalosporin antibiotic without an amino group.

Transport of a new cephalosporin developed for oral use, FK089, has been studied with the rat everted small intestine in vitro. Uptake was found to be pH-dependent with the maximum rate at an acidic pH below 5 and with a 5-fold lower rate at pH 7.0. The shape of the pH-rate profile was very similar to that of cefixime and different from that of pH-lipophilicity profile of FK089. The saturation kinetics of the uptake of FK089 were demonstrated at pH 5.0. By correcting the nonsaturable rate process, the kinetics of the mutual inhibition of FK089 uptake by cefixime and cefixime uptake by FK089 were all consistent with competitive type inhibition. The results indicate that carrier-mediated transport is responsible for transport of cephem antibiotics without an alpha-amino group in the side chain at the 7-position of the cephem nucleus in the intestinal brush-border membrane.

Animals↗
PubMed1985

A carrier-mediated transport system for benzylpenicillin in isolated hepatocytes.

The transport mechanism of benzylpenicillin was studied in freshly prepared rat hepatocytes. The initial uptake rate followed both saturable and unsaturable transport processes. The Arrhenius plot of the initial uptake rate gave an activation energy of 16.8 kcal mol-1 (69 kJ mol-1). The benzylpenicillin uptake by hepatocytes was significantly inhibited by antimycin A, sodium cyanide, rotenone, 2,4-dinitrophenol, phenoxymethylpenicillin, probenecid and taurocholic acid. No significant inhibition was observed by acetylaminohippuric acid and several kinds of amino acids and dipeptides. The present study provides the first evidence for the existence of a carrier-mediated and energy-dependent transport system of benzylpenicillin in the liver.

Animals↗