Nobuyoshi Kaneniwa

Pharmacokinetic study of the fate of acetaminophen and its conjugates in rats

Pharmacokinetic studies of the fate of acetaminophen and its major metabolites, acetaminophen sulfate (AS) and acetaminophen glucuronide (AG), were made in rats. The rates of conjugate formation were calculated by deconvolution. The Michaelis-Menten equation gave maximum velocity and Michaelis constant (Km)values of 4.92 μ-mol/min/kg and 109 μM for AS formation, and 2.76 μmol/min/kg and 915 μM for AG formation. However, AG formation showed approximately first-order behavior in the present dose range because of its large Kmvalue. The disposition of acetaminophen could be described by a two-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics for AS formation. Curve fitting of the data based on this model was successfully done for doses of up to 1058 μmol/kg, suggesting that sulfation proceeds without depletion of sulfate in the blood at least up to this dose. The disposition of AS could be described by a two-compartment model and was apparently dose-independent over an 8-fold dose range. Although a slight dose dependence in the elimination of AG was suggested over a 16-fold dose range, for the purpose of the present study, it was assumed that the disposition of AG is approximately linear. The excretion of AS in the bile was negligibly small, whereas a considerable amount of AG was excreted into the bile. The results following intraduodenal injection of AS or AG indicated that AS or AG was hydrolyzed by the microflora and the liberated acetaminophen was reabsorbed, confirming enterohepatic circulation of the conjugates. This was consistent with the urinary metabolite excretion patterns observed after acetaminophen injection in normal and bile fistula rats. Based on the kinetic parameters obtained, the plasma concentrations of AS and AG after acetaminophen injection were simulated, and a fairly good agreement was obtained between calculated and observed values at the dose of 264.6 μmol/kg. Although the urinary metabolite excretion pattern differs from that of humans, the kinetic parameters obtained for rats were similar to those for humans in some respects, suggesting that the rat might be useful as a model animal to predict human data.

Effect of Surface Characteristics of Theophylline Anhydrate Powder on Hygroscopic Stability

Abstract— The hygroscopicity of theophylline anhydrate has been investigated by gas adsorption and hydration kinetic methods. Type I theophylline anhydrate was obtained by recrystallization from distilled water at 95°C, and type II was obtained by dehydration of theophylline monohydrate. The X‐ray diffraction pattern of types I and II agreed with the data of theophylline anhydrate. However, the diffraction peaks of the (200) and (400) planes of type I were much stronger than those of type II. The particles of type I were clear crystalline‐like single crystals. However, the particles of type II had many cracks. The gas affinity balance (H/N) of type II, measured by gas adsorption, was about 7 times that of type I. After the hygroscopicity of types I and II had been tested at various levels of relative humidity (RH) at 35°C, type I was stable at less than 82% RH, but transformed into the monohydrate at more than 88% RH. Type II was stable at less than 66% RH and transformed into the monohydrate at less than 75% RH. The hydration data of type I at 88% RH and type II at 75% RH were calculated for hydration kinetics using various solid‐state kinetic models, but no particular model could be preferred from these data.

Effects of the Mechanical Energy of Multi‐tableting Compression on the Polymorphic Transformations of Chlorpropamide

The effects of the mechanical energy of tableting compression on the polymorphic transformation of chlorpropamide have been examined. A single‐punch eccentric tableting machine with a load cell and a non‐contact displacement transducer were used to measure compression stress, distance and energy. An amount of 100 mg of the stable form A or the meta‐stable form C of the drug was loaded into the press and the sample compressed with a compression stress of 196 MPa at room temperature (20°C). The compression cycle was repeated from 1 to 30 times. The powder X‐ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The results on forms A and C suggested that both forms were transformed into each other in the solid state by mechanical energy during tableting. The contents of forms A and C reached equilibrium at a constant value above 100 J g−1 of compression energy after more than 10 cycles. After 30 tableting cycles of forms A and C., the contents of A, C and the non‐crystalline solid were almost constant at about 45, 25 and 30%, respectively. The compression energies were estimated to be about 500–600 J g−1. From the results it seems that the transformation mechanism of forms A and C during tableting were as follows. The crystal form of A or C was converted to a non‐crystalline solid by the mechanical energy, and the solid was then transformed into form A or C.

Effects of Temperature and Pressure During Compression on Polymorphic Transformation and Crushing Strength of Chlorpropamide Tablets

Abstract— The effects of temperature on the polymorphic transformation of chlorpropamide during compression and on the physical properties of the tablet have been investigated. A heater and liquid nitrogen pool were mounted on the die of a single punch eccentric tableting machine, and the die temperature was controlled by a thermocontroller. A tableting machine with two load cells (upper and lower punches) and a non‐contact displacement transducer were used to measure compression stress, distance and energy. The X‐ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The amount of form C transformed from form A at 45°C was about twice that at 0°C with the same compression energy. The amount of form A transformed from form C by compression at 45°C was almost the same as that at 0°C. This suggests that the mechanochemical effect of form A depended on the compression temperature, but that of form C was independent of temperature. The crushing strength of tablets of form A was about twice that of form C, even at the same porosity. The plots of log (crushing strength of tablet) against porosity of form A tablets compressed at 0 and 45°C were linear with the same slope; the slope for form C tablets compressed at 45°C was less than that at 0°C.

Relation Between Polymorphic Transformation Pathway During Grinding and the Physicochemical Properties of Bulk Powders for Pharmaceutical Preparations

AbstractThe polymorphic transformation pathway during grinding of cephalexin (CEX), chloramphenicol palmitate (CPP) and indomethacin (IMC) were investigated. CEX was converted into noncrystalline solid at room temperature. The meta-stable forms B and C CPP was transformed into stable form A at room temperature. IMC was transformed into noncrystalline solid during grinding at 4°C, but it transformed into meta-stable form a during grinding at 30°C. The melting point (mp) of CPP and IMC were about 90°C and 160°C, respectively. CEX does not have the mp, but have the decomposition point at 190°C. The mp of CEX is higher than the decomposition point. The order of the mp for these drugs is CPP < IMC < CEX. The proportional relation between the mp and the glass transition point of the drugs had reported, therefore, in general the higher mp material has the higher glass transition point. The order of the stability for a noncrystalline solids of these drugs is CPP < IMC < CEX. The noncrystalline solid of CEX is ver...

Nonlinear assessment of nitrofurantoin bioavailability in rabbits

The influence of route of administration on the absolute bioavailability and GI tract absorption of nitrofurantoin was investigated in rabbits. The disposition of nitrofurantoin was described by a one-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics, and bioavailability was estimated by nonlinear assessment. The plasma levels following oral administration were significantly lower than those after intravenous administration, and absolute Fvalues for oral administration were approximately 0.3. However, Fvalues following intraduodenal administration and portal vein infusion were nearly unity, and it was concluded that the reduction of bioavailability following oral administration could not be attributed to metabolism by intestinal microflora or to the hepatic first-pass effect. Thus, reduction of Fvalues following oral administration is probably due to gastric degradation of the drug. The effects of factors influencing bioavailability, such as water volume taken with the drug, change of gastric emptying rate and effect of particle size, were also investigated. Increase of volume of water administered tended to improve the bioavailability, and a particle size dependency was also observed.

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.

Effects of Tableting Pressure on Hydration Kinetics of Theophylline Anhydrate Tablets

Abstract— The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35°C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37‐16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two‐dimensional phase boundary equation (type I tablets) or the three‐dimensional phase boundary equation (type II tablets).

Analysis of the absorption characteristics of cimetidine with the use of the multi-segment absorption model

Abstract Compartment model analysis is able to determine the mean transit time of drugs in the gastrointestinal tract, but it must be assumed that the movement of drugs is approximately first-order in the gastrointestinal tract, as reported previously. The multi-segment absorption model does not need such a first-order approximation. We applied this model to clarify the effects of metoclopramide and atropine on the absorption of cimetidine. The initiation times of absorption at the duodenum and the jejunum were decreased 0.5-fold by metoclopramide but increased 4-fold at the duodenum and 2-fold at the jejunum by atropine. The initiation time of absorption at the ileum was not changed in the cases of control and coadministration of metoclopramide when it was corrected for lag time. These findings were consistent with the results of intestinal motility measurement by γ-scintigraphy. Calculated plasma concentrations based on the multi-segment absorption model were well correlated to the observed values. Consequently, it was suggested that the multi-segment absorption model is reliable and that this model would be useful to analyze in detail the gastrointestinal absorption of drugs such as cimetidine, in which the optimal absorption site is the ileum.

Effect of Environment on Crystallinity and Chemical Stability in Solid-State of Ground Cephalotin Sodium During Storage

AbstractEffects of environmental conditions on the crystallinity and the decomposition point (Dp) of ground cephalotin sodium during storage were investigated by X-ray diffraction and differential thermal analysis (DTA). The X-ray diffraction peaks of ground products increased after storage at 0% and 75% relative humidity (R.H.), at 35° C. The crystallinity of ground product increased at 75% R.H. and 0% R.H., 35°C, but that of ground product at 0% R.H., -30°C was not changed. The Dp measured by DTA of the ground product increased from 189.5°C to 197°C after 4 days at 75% R.H., but the Dp of the ground product at 0% R.H., -30°C for 4 days was 190.1°C. Relation between the Dp and the crystal Unity of ground cefalotin sodium was a straight suggesting that the thermal stability of cefaiotin sodium in the solid-state depends on the degree of crystallinity.