Search PubMed⌕ Search

Biomedical subjects

E Nakashima

Publications and source records attributed to E Nakashima.

122 records · Page 7Linked to original sources
PubMed1983

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats.

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.

Animals↗
PubMed1981

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-beta-lactam antibiotics by in situ rat small intestine.

The disappearance of various beta-lactam antibiotics from in situ rat small intestinal loops was studied at pH 7.4. For monobasic penicillins, despite the wide variety of apparent partition coefficients in isobutyl alcohol-water, the disappearance from the jejunal loops was almost 30% (+/- 5% SD). On the other hand, the disappearance of amphoteric derivatives of penicillins and cephalosporins having very low lipid solubility varied widely between 12 and 80%. The peak blood levels after intraduodenal administration to the rats correlated well with the extent of disappearance of amphoteric penicillins from the intestinal loops. Absorption studies utilizing in situ intestinal loops were performed at variable dose ranges to yield a clear dose-dependent disappearance. It is suggested that certain carrier-mediated transport systems underlie the absorption mechanism of amphoteric beta-lactam antibiotics.

Animals↗
PubMed1981

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics II: Michaelis-Menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats.

The absorption of cyclacillin at pH 7.0 by the rat small intestine was investigated using in situ perfusion. At the lowest dose of 95 microgram/ml, the antibiotic disappearance was rapid and followed first-order kinetics, with the disappearance being 85% at 100 min. At the intermediate concentrations of 770 and 1200 microgram/ml, the disappearance after 100 min was 69 and 54%, respectively, and semilogarithmic plots clearly showed convex curvatures. At the highest concentration of 30 mg/ml, cyclacillin disappeared slowly from the perfusate, in an apparent first-order fashion. The disappearance was 26% after 100 min of perfusion and was similar in extent at 5.2 mg/ml. This concentration-time profile was satisfactorily fitted to the simultaneous Michaelis-Menten and first-order kinetic equations. The area under the blood concentration versus time curve (AUC) after a single intraduodenal dose of cyclacillin was almost consistent with the AUC after the equivalent intravenous dose (10 mg/kg). Additional evidence from a pharmacokinetic analysis of steady-state blood concentrations after constant infusion of cyclacillin through the portal vein and the small intestinal lumen indicated that cyclacillin absorption by the rat intestinal tissue at relatively low concentrations (less than 1 mg/ml) followed solely Michaelis-Menten kinetics. Cyclacillin may be transported by certain types of carrier-mediated mechanisms.

Animals↗
PubMed1981

Degradation kinetics and mechanism of aminocephalosporins in aqueous solution: cefadroxil.

The degradation kinetics and mechanism of a new, orally effective cephalosporin derivative, cefadroxil, in aqueous solution were investigated at pH 2.51-11.5 at 35 degrees and ionic strength 0.5. The degradation rates were determined by high=pressure liquid chromatography. At constant pH and temperature, the degradation followed first-order kinetics and a log k-pH profile was presented. The shape of the rate-pH profile resembled that for cephalexin or cephradine under the same conditions. Citrate and phosphate buffers enhanced general acid and base catalysis of the degradation. In aqueous solution, cefadroxil was shown to degrade by three parallel reactions: (a) intramolecular aminolysis by the C-7 side-chain amino group on the beta-lactam moiety, (b) water-catalyzed or spontaneous hydrolysis, and (c) beta-lactam cleavage by the nucleophilic attack of hydroxide ion. In neutral and weak alkaline solutions, the main degradation products were two piperazine-2, 5-diones and 3-hydroxy-4-methyl-2(5H)-thiophenone, the former being formed from Reaction a, while the latter arose via the degradation pathways of Reaction b and/or c.

Buffers↗
PubMed1979

Physicochemical properties of amphoteric beta-lactam antibiotics. II: Solubility and dissolution behavior of aminocephalosporins as a function of pH.

The solubility of aminocephalosporins in aqueous solution at 37 degrees and an ionic strength of 0.5 exhibited U-shaped curves against pH. At their isoelectric pH, cephradine monohydrate was the most soluble, followed by cephalexin monohydrate and cephaloglycin dihydrate, with intrinsic solubilities of 26.0, 17.2, and 14.8 mg/ml, respectively. The dissolution rate constants from the rotating disk were also determined as a function of the pH of the dissolution medium and interpreted reasonably by the simultaneous dissociation equilibrium reaction and the diffusion kinetics model. Energies for the solubility and dissolution were determined for these three aminocephalosporins.

Cephalexin↗
PubMed1978

Physicochemical properties of amphoteric beta-lactam antibiotics I: Stability, solubility, and dissolution behavior of amino penicillins as a function of pH.

The degradation rate, solubility, and dissolution rate of amino penicillins, amoxicillin, ampicillin, epicillin, and cyclacillin, were determined quantitatively as a function of pH. In the pH range studied, 0.30-10.50, the degradation of amoxicillin and epicillin followed pseudo-first-order kinetics to give the same type of pH-rate profiles as those of ampicillin and cyclacillin. Cyclacillin anhydrate was the most soluble, followed in order by ampicillin anhydrate, ampicillin trihydrate, amoxicillin trihydrate, and epicillin anhydrate. These pH-solubility profiles showed showed U-shaped curves. The dissolution rate constants from the rotating disk were analyzed by the simultaneous chemical reaction and diffusion models. Their relative bioavailability after a single oral administration was assessed from their physicochemical properties determined in vitro.

Chemical Phenomena↗
PubMedDate not supplied

A physiologically based pharmacokinetic model for (-)-quinuclidinyl benzylate using nonlinear irreversible tissue binding parameters in rats.

The disposition characteristics of (-)-quinuclidinyl benzylate (QNB) were investigated in rats, and a physiologically based pharmacokinetic model was established using its linear and nonlinear tissue binding parameters. The steady-state distribution volume (Vdss) and systemic clearance (CLtot) were comparable after iv administration of 325 ng/kg and 3.2 mg/kg, suggesting that QNB pharmacokinetics based on plasma concentrations is linear. However, tissue accumulation was observed in the heart, lung, muscle, and brain. This accumulation persisted for over 12 hr after the iv administration of 325 ng/kg [3H]QNB. Tissue binding parameters were determined after continuous infusion of QNB. Irreversible and nonlinear binding parameters were obtained in various regions of the brain and other tissues. Reversible equilibrium concentration ratios between tissue and plasma were determined after high-dose infusion. QNB concentrations in the plasma, heart, lung, muscle, and brain were predicted after the administration of 325 ng/kg or 3.2 mg/kg. There was reasonable agreement between the model predictions and the observed data.

Animals↗
PubMedDate not supplied

Comparative pharmacokinetics of cefoperazone and cephradine in untreated streptozotocin diabetic rats.

Experimental diabetes mellitus was induced in adult male rats by injecting streptozotocin (STZ; 60 mg/kg iv) for the purpose of surveying changes in the pharmacokinetics of biliary excretion after the intravenous administration of 40 mg/kg of cefoperazone (CPZ) or cephradine (CED). CPZ, CED, and other organic anions share affinity for the organic anion transport system in the bile canalicular membrane. The STZ treatment had a marked influence on the distribution and elimination of both cephalosporins. The blood levels of both cephalosporins at each time point after administration differed significantly between the STZ-treated and control rats. The values of mean residence time (MRT) of CPZ and CED were significantly decreased in the STZ-treated rats. Basal bile flow rates were increased after the administration of CPZ in the control and STZ-treated rats. Biliary clearance (CLbile) of CPZ was more than 60% of the CLtot, whereas CLbile of CED was less than 20% of CLtot in both groups of rats. The mean CLbile value of CPZ in the STZ-treated rats was 1.0 ml/min higher than that of the control rats, whereas the mean CLbile value of CED was almost the same as that of the control rats. The increased CLbile of CPZ suggested that diabetes alters the biliary excretion of CPZ. The changes in MRT of CPZ in the STZ-treated and control rats are mainly caused by an increase in the biliary excretory rate and renal clearance. The changes in MRT of CED in the STZ-treated and control rats are caused by a decrease in the apparent volume of distribution and increased renal clearance.

Animals↗
PubMedDate not supplied

Effect of fat tissue volume on the distribution kinetics of biperiden as a function of age in rats.

The relationship between the volume of fat tissue and variations in the time course of plasma biperiden concentration in rats has been examined in three different groups (4-, 10-, and 50-week-old rats). The plasma concentrations at 24 hr after iv injection of 3.2 mg/kg varied between 0.8 ng/ml (4-week-old rats) and 5.0 ng/ml (50-week-old rats). The rank order of the steady state distribution volume of biperiden was: 50-week-old rats greater than 10-week-old rats greater than 4-week-old rats. The fat volume of the whole body, extracted from the dried carcass with ether, varied between 42 g/kg (4-week-old rats) and 167 g/kg (50-week-old rats). There was a good correlation between the steady state distribution volume of biperiden per lean mass body weight and the fat volume per lean mass body weight (r = 0.987). The fat/plasma concentration ratios at 8 hr after the iv injection varied between 600 (4-week-old rats) and 200 (50-week-old rats), whereas the brain/plasma concentration ratios were identical to those at steady state among the three groups. The time courses of biperiden concentration in plasma, brain, and fat were simulated using a physiological pharmacokinetic model. There was reasonable agreement between the model predictions and the observed data, suggesting that the change in the fat volume is a dominant determinant of the distribution volume of biperiden in rats. Age-related changes in tissue and plasma concentrations are discussed in relation to the clinical usefulness of the blood level monitoring.

Adipose Tissue↗
PubMedDate not supplied

Physiologically based pharmacokinetic model for cefazolin in rabbits and its preliminary extrapolation to man.

In the present study, the physiologically based pharmacokinetic model, which succeeded previously in predicting the pharmacokinetics of beta-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C.H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for beta-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and inulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period for the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.

Animals↗