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Biomedical subjects

E Nakashima

Publications and source records attributed to E Nakashima.

At least 109 records · Page 6Linked to original sources
PubMed1987

Comparative distribution kinetics of cefazolin and tobramycin in children.

The time courses of drug concentration in serum after i.v. drip infusion of 2 mg/kg of tobramycin and 25 mg/kg of cefazolin in children were analyzed by model-independent moment analysis. The volume of distribution at the steady state per body weight (Vdss/BW) of tobramycin was in the range of 212 to 335 ml/kg and that of cefazolin was 119 to 156 ml/kg. A plot of the differences of Vdss/BW obtained in the same child for tobramycin and cefazolin against the value of Vdss/BW of tobramycin gave a linear regression line (r = 0.971). The magnitude of Vdss (1) of tobramycin could be well interpreted as corresponding to the extracellular water volume. In the case of cefazolin, the extracellular water space accounts for about 60% of the total distribution volume. The remaining 40% of the total Vdss of cefazolin was considered to be accounted for by the disposing organs.

Blood Proteins↗
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

Fundamental pharmacokinetic properties of biperiden: tissue distribution and elimination in rabbits.

The pharmacokinetics of biperiden in rabbits were examined at three doses (0.2, 0.8, and 3.2 mg/kg i.v.). The data were interpreted in terms of a three-compartment open model with a linear excretion rate. The serum unbound fraction and the blood-to-plasma concentration ratio were determined as 0.39 and 1.2, respectively, over a wide concentration range (25-10000 ng/ml). Rapid and complete absorption from the injection site in muscle to the systemic circulation was observed. The bioavailability of muscular injection was unity. The hepatic extraction ratio was 0.94, and the high plasma clearance could be explained in terms of hepatic blood flow rate-limited elimination. The major tissues in which biperiden was distributed were fat and muscle. The highest tissue-to-plasma partition coefficient in the steady-state was obtained for the lung. These three tissues comprised 56% of the total distribution volume.

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↗
PubMed1985

Effect of extracellular water volume on the distribution kinetics of beta-lactam antibiotics as a function of age.

The distribution kinetics of cefazolin in rats has been examined at four different ages (1, 7, 50 and 100 weeks). The steady state distribution volume of cefazolin, estimated from the plasma time course after i.v. injection of 20 mg/kg, varied between 136 ml/kg (50-week-old rats) and 297 ml/kg (1-week-old rats). The extracellular fluid volume, obtained from the steady state distribution volume of inulin, varied between 126 ml/kg (50-week-old rats) and 370 ml/kg (1-week-old rats). There was a good correlation between the steady state distribution volume of cefazolin and extracellular fluid volume (r = 0.977). The influence of changes on the value of the plasma unbound fraction and extracellular fluid volume on the tissue-to-plasma partition coefficient of beta-lactam antibiotics was simulated by using a physiological pharmacokinetic model. The results of the simulation showed that extracellular fluid volume is an important factor affecting the distribution volume of beta-lactam antibiotics and that plasma binding plays a minor role on it. The experimental and simulation results suggested that the change in the interstitial fluid volume is a determinant factor in the age-related changes in the distribution volume of beta-lactam antibiotics.

Aging↗
PubMed1985

Mutual effects of amino-beta-lactam antibiotics and glycylglycine on the transmural potential difference in the small intestinal epithelium of rats.

The transport mechanism of amino-beta-lactam antibiotics across in vitro rat ileum was examined using the electrophysiological technique in comparison with that of dipeptides. The changes in the transmural potential difference (PDt) induced by a series of amino-beta-lactam antibiotics were correlated with the absorption percentage of these antibiotics from the in situ rat intestinal loops. On the contrary, beta-lactam antibiotics without alpha-amino group such as dicloxacillin, methicillin and cefazolin did not induce such a stable change of PDt. The changes in PDt induced by cyclacillin (ACPC), cefadroxil (CDX) and glycylglycine (Gly-Gly) became saturable when the concentration of the substances increased. The half saturation concentration for ACPC, CDX, and Gly-Gly estimated from the changes in PDt was nearly identical with that determined from influx of the substrates in the everted intestinal sacs. The mutual inhibition between amino-beta-lactam antibiotics and Gly-Gly was observed in their induced PDts. The changes in PDt induced by amino-beta-lactam antibiotics were independent of those of glucose, glycine, and cefazolin. By the removal of Na+ from the mucosal solution, the PDt decreased one-fifth of the PDt induced in the presence of Na+. These results suggest that amino-beta-lactam antibiotic-induced PDt relates to the Na+ ion fluxes as reported for dipeptides.

Animals↗
PubMed1985

A parallel analysis of cancer mortality among atomic bomb survivors and patients with ankylosing spondylitis given X-ray therapy.

Radiation-induced cancer mortality rates among atomic bomb survivors with doses of at least 100 rad and patients with ankylosing spondylitis given X-ray therapy have been compared for the first time. The estimated average mean bone marrow dose for the spondylitics is more than twice that for atomic bomb survivors, and yet spondylitics experienced only half the risk of radiation-induced leukemia of atomic bomb survivors. For sites that were heavily irradiated in the spondylitics, provisional estimates indicate comparable doses in the two studies, and similar levels of cancer risk were observed. For these sites, when information from the studies was combined, there were statistically significant excesses for cancers of the esophagus, stomach, lung, and ovaries, multiple myeloma, other lymphomas, and tumors of the spinal cord and nerves. Very high relative risks (RR's) for tumors of the spinal cord and nerves were observed in both studies. For sites that were lightly irradiated in the spondylitics, in addition to previously documented sites, there was a statistically significant excess of cancers of the liver and gallbladder among atomic bomb survivors. A previous subdivision of cancer sites into radiosensitive and other tissues was not supported by the atomic bomb survivor data. Changes in the rates of radiation-induced cancers with age at exposure and time since exposure were studied and compared with the use of generalized linear modeling of the RR's and also by examination of the excess mortality rates. The level of agreement between the two studies was high; provided it is accepted that the reduced level of leukemia risk in the spondylitics is due to cell sterilization, no inconsistencies were found. For a group of solid tumors selected from heavily irradiated sites in the spondylitics, excess risk increased with both age at exposure and time since exposure and RR decreased with age at exposure, but it did not vary with time since exposure between about 5 and at least 30 years following exposure. The finding of a constant RR with time since exposure did not extend to all remaining neoplasms other than leukemia, because the RR for these neoplasms increased with time since exposure in atomic bomb survivors.

Age Factors↗
PubMed1984

Kinetics and mechanism of in vitro uptake of amino-beta-lactam antibiotics by rat small intestine and relation to the intact-peptide transport system.

By utilizing the everted jejunum of rats, the initial uptake rates of several antibiotics were measured over a wide range of concentrations. The uptakes followed mixed-type kinetics involving saturable and non-saturable processes in parallel. The pertinent kinetic parameters for the uptake of each antibiotic were determined. The effect of cephalexin on the uptake of cyclacillin obeyed competitive inhibition kinetics, and the inhibition constant Ki was found to be equal to the Michaelis constant Kt for the uptake of cephalexin itself. In a similar way, the uptake of cephalexin was inhibited by cyclacillin. Uptakes of both cyclacillin and cephalexin were reduced significantly by several metabolic inhibitors. From the effect of temperature on the uptakes of cyclacillin and cephalexin, activation energies of 24.8 and 23.1 kcal/mole were obtained respectively. These results indicate the involvement of an active transport mechanism for cyclacillin and cephalexin. It was found that several dipeptides markedly inhibited the uptakes of cyclacillin and cefadroxil. Furthermore, the uptake of glycylglycine, a typical dipeptide, was inhibited by cyclacillin, cefadroxil, cephalexin, and cephradine. The kinetics of mutual inhibition of the uptakes of cyclacillin and glycylglycine were consistent with competitive-type inhibition. This is the first report which establishes, from a kinetic point of view, the involvement of a common transport system in the in vitro uptakes of the dipeptides and the antibiotics.

2,4-Dinitrophenol↗
PubMed1984

Microbial kinetics of beta-lactam antibiotics against Escherichia coli.

Microbial kinetics of Escherichia coli NIHJ JC-2 and E. coli B/r were investigated in the presence of beta-lactam antibiotics. To maintain a constant drug concentration during the experiment, a novel technique, using a dialysis membrane tube containing the drug solution, was successfully employed. The drug-affected generation curves of E. coli exhibited common features. After the addition of drug, an apparent lag period was noted, followed by a first-order decrease of the sensitive organisms and, 6 h later, by a regrowth of resistant organisms, depending on the antibiotic concentration used. The relationship between the apparent generation rate constant, kapp, and the antibiotic concentration was found to be nonlinear. This phenomenon is consistent with a saturable receptor site model for the drug action. A good linear free energy relationship was observed between the microbial kinetic parameter, kmax, and the alkaline degradation rate constants, kOH, of the cephalosporins studied.

Anti-Bacterial Agents↗
PubMed1984

Kinetic analysis and characterization of the bacterial regrowth after treatment of Escherichia coli with beta-lactam antibiotics.

The generation curves of Escherichia coli B/r and E. coli NIHJ JC-2 in the presence of several beta-lactam antibiotics were studied from the kinetic point of view. Apparent first-order regrowth of resistant organisms was observed approximately 6 h after addition of these antibiotics. The time courses of apparent viable counts could be interpreted in terms of the sum of the viable counts of sensitive and resistant organisms. To clarify the nature of the regrowth, experiments involving a second addition of antibiotic, single colonization by subculture, and synchronous cell culture were carried out. Several possible explanations for the results are discussed, including beta-lactamase production, selection in terms of membrane permeability, and mutation to acquire drug resistance. A selection process or a modification of membrane permeability caused by contact with the drug seems to be the most probable reason for the regrowth of the organisms.

Ampicillin↗
PubMed1984

Intestinal absorption mechanism of amino-beta-lactam antibiotics. III. Kinetics of carrier-mediated transport across the rat small intestine in situ.

The transport kinetics of amino-beta-lactam antibiotics was studied by an in situ rat small intestinal recirculating perfusion technique. The disappearance rates of the antibiotics from the perfusing luminal solution followed mixed-type kinetics with saturable and nonsaturable processes. The kinetic parameters were determined. Pharmacokinetic analysis of the time courses of luminal disappearance, tissue accumulation, and blood concentration indicated that the transfer of the antibiotics from the in situ luminal solution to tissue is nearly irreversible. On the assumption that the saturable transport process involves a common carrier for these antibiotics, the predicted extents of mutual inhibition using the in situ kinetic parameters were in good agreement with the experimental values for cephalexin and cephradine. The effects of cephalexin and cefadroxil on the absorption of cyclacillin were also consistent with a common transport mechanism. The dipeptides, carnosine and L-phenylalanylglycine markedly inhibited cyclacillin absorption in a competitive fashion. Furthermore, cyclacillin inhibited the absorption of carnosine. The results indicate that the absorption of amino-beta-lactam antibiotics is closely related with that of dipeptides.

Animals↗