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N Kaneniwa

Publications and source records attributed to N Kaneniwa.

At least 37 records · Page 2Linked to original sources
PubMed1987

Pharmacokinetic study of carbamazepine and its epoxide metabolite in humans.

A major metabolite of carbamazepine (CBZ), CBZ-10, 11-epoxide (EPO), has been reported to possess anticonvulsant properties. Therefore, the present study was undertaken in order to develop a pharmacokinetic model to predict the behavior of EPO in the body after administration of CBZ. The serum concentration-time curves after oral administration of solution of CBZ (200 mg) or EPO (150 mg) in six healthy subjects showed the characteristic "nose", suggesting that disposition of CBZ or EPO could be described by the two-compartment model. The kinetic parameters of disposition for CBZ and EPO were calculated by the method of Wagner, assuming the absolute bioavailabilities of CBZ and EPO to be 1.0 and 0.81, respectively. Total body clearance and elimination rate constant of EPO were very much larger than those of the parent drug but there was no statistically significant difference in the distribution volume between CBZ and EPO. The formation rate of EPO was calculated by a deconvolution method, and obeyed Michaelis-Menten kinetics. Based on these findings, a pharmacokinetic model of the fate of CBZ and EPO in humans was developed and the time courses of CBZ and EPO in serum after oral administration of three tablet preparations and a solution containing 200 mg of CBZ were simultaneously fitted to this model by solving the differential equations by the Runge-Kutta-Gill method. There was good agreement between calculated and observed serum values, suggesting that the present model is appropriate to describe the formation and disposition of EPO from CBZ. The formation rate constant of EPO (Vmax/Km/V1) was approximately one-fifteenth of the elimination rate constant of EPO. This suggested a flip-flop model in which the formation of EPO was rate-limiting in humans. The observation that the serum concentrations of EPO after administration of CBZ were one-tenth to one-twentieth of those of the parent drug was well explained by the flip-flop kinetics of EPO, together with the large differences in total body clearance and elimination rate constant between CBZ and EPO.

Adult↗
PubMed1986

Effect of seed crystals on solid-state transformation of polymorphs of chloramphenicol palmitate during grinding.

The polymorphic transformations of chloramphenicol palmitate, (2R, 3R)-2-(2,2-dichloroacetamido)-3-hydroxy-3-(4-nitrophenyl) propyl palmitate (1), during grinding in an agate centrifugal ball mill at 200 rpm, and the effect of seed crystals on the transformation were studied by means of X-ray diffraction analysis, differential scanning calorimetry, and scanning electron microscopy. The transformation was analyzed using the kinetic method based on nine kinetic model equations. Form B of 1 was transformed to form A (the therapeutically least active form) during grinding for more than 150 min, but in the presence of 1% of form A as seed crystals, form B was transformed to form A during grinding for 40 min. The transformations of form B during grinding in the absence and in the presence of seed crystals were fitted to the two-dimensional nuclear growth equation (Avrami equation). Form C was transformed to form B during grinding for 16 min (and then to form A when grinding was continued for a total of 160 min). The transformation of form C to form B during grinding was accelerated by the presence of 1% of form B, while the subsequent transformation to form A was unaffected, as expected. On the other hand, in the presence of 1% of form A, both the transformation of form C to form B and the subsequent transformation to form A were completed within a grinding time of only 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry, Differential Scanning↗
PubMed1986

Study of the absorption site of cimetidine.

The optimal absorption site of cimetidine was assessed in rats. The ileac pH value (measured by a pH meter with a micro pH combination electrode) was slightly higher than that in other intestinal sites, and the absorption rate constant (ka) following the administration of cimetidine into the ligated ileac loop was larger than that in the ligated duodenal and jejunal loops. It is suggested that the ileum is the optimal absorption site of cimetidine. On administration of cimetidine into the ligated and unligated intestines, the ka values of either the duodenum or the ileum were found to be almost the same between the ligated and unligated cases. However, the ka value of the jejunum in the unligated case was slightly larger than that in the ligated case. Thus, it is suggested that cimetidine is completely absorbed in the duodenum and ileum during its passage through these intestinal sites, but at the jejunum an unabsorbed fraction of cimetidine passes to the ileum, where it is absorbed completely. Based on these results, a pharmacokinetic model for the absorption of cimetidine following oral administration was designed, in which gastric, duodenal, jejunal, and ileac compartments were included separately but enterohepatic circulation was not included, because the biliary excretion of cimetidine following intravenous and oral administrations were generally lower than 2% of the dose. The value of k41 was ca. 4 times larger than that of k45, and the value of k45 could be approximated to zero in the model.

Animals↗
PubMed1986

Three-compartment open model analysis of micronomicin in man.

The pharmacokinetics of micronomicin (MCR) as a model drug of aminoglycoside antibiotics (AGs) was studied in man by applying our results previously obtained in rats. Three-compartment open model analysis of combined serum and total body store (T.B.S.) data obtained from multiple dosing in man was done using a non-linear least-squares regression program MULTI. We found large individual variations of MCR disposition in man and these variations did not appear within the serum concentration range measurable with conventional assay methods. This finding suggests that the disposition of AGs, included MCR, cannot be estimated by only plasma or serum level analyses. We conclude that the therapeutic drug monitoring of AGs by using T.B.S. data analysis should be an effective method for controlling therapy with AGs in the clinical setting.

Adult↗
PubMed1986

Effect of metoclopramide on the absorption of cimetidine in rats.

Metoclopramide was found to increase the absorption rate constant (ka) of cimetidine by the duodenum and jejunum in both ligated and unligated rats. The increase of ka of cimetidine in the ligated rats cannot be interpreted in terms of an increase in the gastric emptying rate, which has been suggested to be the main effect of metoclopramide. The pH values of the stomach, duodenum and jejunum increased following the administration of metoclopramide. Atropine also increased the pH value of the duodenum, but it did not increase the ka of cimetidine. Consequently, the increase of ka of cimetidine, following administration of metoclopramide, was not due to the elevation of intestinal pH. On the other hand, metoclopramide significantly increased the blood flow by about 67.3 and 29.7% at the duodenum and jejunum, respectively, when the intestinal blood flow was measured by the hydrogen clearance method. Atropine had no effect on the intestinal blood flow. Based on these results, it was concluded that the increase of intestinal blood flow may be one of the factors for the increase of ka of cimetidine following the administration of metoclopramide. From the results of multi-line fittings of the plasma concentration data following oral, intraduodenal, intrajejunal and intraileac administrations of cimetidine with metoclopramide treatment, it was suggested that metoclopramide increased the intestinal transit time of subsequently administered drugs, as well as the gastric emptying rate.

Animals↗
PubMed1985

Dose- and time-dependent kinetics of the renal excretion of nitrofurantoin in the rabbit.

A pharmacokinetic study on the renal excretion of nitrofurantoin was carried out in rabbits at doses ranging from 0.5 to 15 mg/kg. With increasing dose, nonlinear kinetics were observed in the tubular secretion, which appeared to show dose and time dependence. The disposition of nitrofurantoin after intravenous injection is well described by a one-compartment model with simultaneous first-order nonrenal elimination and renal elimination, which consists of glomerular filtration, active tubular secretion conforming to the Michaelis-Menten equation, and reabsorption clearance by nonionic diffusion. Plasma and urinary excretion data after intravenous injection of nitrofurantoin were fitted to this model. When the Michaelis constant was loosely restricted at a constant value, the maximum velocity decreased with increasing dose of nitrofurantoin. However, the Michaelis constant apparently increased with increasing dose when the maximum velocity was loosely restricted at a constant value. Although the results of this fitting suggested that the former case may occur in the active tubular secretory system, the latter case could not be completely eliminated because of limited data. The implications of these results are discussed on the basis of the available published data.

Absorption↗
PubMed1984

Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs in rabbits from the in vitro dissolution behavior.

Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs from data obtained in in vitro dissolution tests of drug suspensions was studied in the rabbit. The relationship between in vivo and in vitro dissolution rates or between absorption rate and in vitro dissolution rate was investigated. The drug absorption from aqueous solution was suggested to be rate-limited by the gastric emptying rate because the initial absorption rate constant in a biexponential time course of aqueous solution for the amount unabsorbed vs. time plot was almost the same among 9 of the 10 drugs tested, except for sulfacetamide. This indicated that when the in vivo dissolution rate constant is much slower than the initial absorption rate constant of aqueous solution, the time course of blood levels for the solid drug will deviate from that of aqueous solution. Based on the consideration, the critical in vitro dissolution rate constant corresponding to the initial absorption rate constants of aqueous solution was calculated by means of statistical analysis using the relationship between in vivo and in vitro parameters. The validity of this prediction was examined using four high-solubility drugs, and it was found that the prediction could be done whether the in vitro dissolution medium was distilled water or 0.1 N HCl solution. Although in the present study, the experiment was done using an aqueous suspension form in the rabbit, the applicability of this prediction method to other dosage forms and to the case of humans is discussed.

Absorption↗