Bioavailability of pyridoxal phosphate from enteric-coated tablets. I. Apparent critical dissolution pH and bioavailability of commercial products in humans.
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Adult↗
Biomedical subjects
N Kaniwa
Publications and source records attributed to N Kaniwa.
Bioavailability of indomethacin capsules in humans. (I): Bioavailability and effects of gastric acidity.
The bioavailabilities of five indomethacin capsules, two commercial and three experimental products, were studied in ten human subjects. The bioavailabilities of the products increased in proportion to their in vitro dissolution rates, although one of the commercial products provided a relatively lower bioavailability than was expected. Comparison of the bioavailabilities between high and low gastric acidity humans revealed that the serum levels of the drug during the absorption phase following oral administration of all the indomethacin products, except for one commercial product, were higher in the low acidity subjects than in the high acidity subjects. Also, the mean peak serum level of the most rapidly dissolving product was 1.6 times higher in the low acidity subjects than in the high acidity ones. These gastric acidity effects indicated enhanced dissolution of indomethacin from the capsules in the stomach of low acidity humans.
Adult↗
Bioavailability of indomethacin capsules in humans (II): correlation with dissolution rate.
The correlation between the dissolution rate and bioavailability in humans for five indomethacin capsules was investigated. The mean Cmax, Tmax and AUC24 of low gastric acidity in humans correlated well with the dissolution rate determined by the paddle method using a slow stirring rate. The Cmax of the high acidity subjects also correlated with the dissolution rates determined under mild conditions. However, the Tmax correlated with the dissolution rates determined under vigorous ones. The in vivo-in vitro correlation seems to have become complicated by an anomalous product whose dissolution was remarkably sensitive to environmental conditions. The correlation data also suggested that the deaggregation force on the adhesive agglomerate in human digestive tract might not be strong.
Biological Availability↗
Bioavailability of indomethacin capsules in humans (III): Correlation with bioavailability in beagle dogs.
The bioavailabilities of five indomethacin capsules were studied in ten beagle dogs and correlations with the in vivo results in humans and dissolution rates were investigated. The difference in bioavailability between two commercial products was smaller in dogs than in humans, which seemed to be due to strong disintegration forces in dogs. The difference in the dissolution rate among the products was reflected less in the Tmax in dogs than in humans, and the Tmax was shorter in dogs which seems to be due to faster gastric emptying and passage of the drug through the absorption site in dogs. Gastric acidity effects on the indomethacin availability found in humans were not observed in dogs. The Cmax and Tmax correlated well with the in vitro dissolution rates, but AUC24 did not. The Cmax and Tmax in dogs also correlated with the corresponding parameters in humans, especially those in high gastric acidity humans, but AUC24 did not.
Animals↗
Bioavailability of griseofulvin plain tablets in stomach-emptying controlled rabbits and the correlation with bioavailability in humans.
Bioavailability after giving oral doses of 62.5 mg griseofulvin tablets having different dissolution rates to stomach-emptying controlled rabbits, was estimated and compared with that in humans receiving 125 mg dose of the same griseofulvin preparations. The relative differences in Cmax and AUC infinity between the product with the highest availability and others tended to be greater in rabbits than in humans. The in vivo parameters correlated well between the two species. However, power analysis indicated a larger variability of Cmax in rabbits than in other species (dogs, minipigs and humans). Water volume (5 and 50 ml) coadministered with the drug did not significantly influence the bioavailability. The rabbits which were not given food after oral dosing with griseofulvin exhibited a lower Cmax than those which were fed immediately after dosing. The bioavailability of an ultramicronized formulation in rabbits was higher after the postprandial dose than after the preprandial dose. Food intake just after the drug administration seems to be an important factor for controlling the passage rate of the drug through the gastrointestinal tract in stomach-emptying controlled rabbits.
Animals↗
Development and evaluation of a new peroral test agent GA-test for assessment of gastric acidity.
A new peroral test capsule, GA-Test, containing riboflavin (5 mg) granules coated with polyvinylacetal diethylaminoacetate (AEA) for assessing gastric acidity without intubation was developed and evaluated for usefulness. GA-Test is based on the tracing in the urine of riboflavin, which is released in the stomach only in the presence of acidic fluid and is absorbed. Due to the film coating, riboflavin released very quickly at a pH of less than 5, and not at all at a pH of greater than 6. GA-Test gave a significant correlation, quantitatively, with peroral Gastrotest in assessing acidity, a non-intubation method which had been marketed in Japan prior to 1980. GA-Test results allowed division of the subjects into two groups i.e., subjects having low (hypo- or anacidity) gastric acidity and those having high (normal or hyperacidity) gastric acidity, GA-Test results agreed well with results of intubation (around 91.4%; 32 out of 35 cases) and were easily reproduced during the evaluation.
Adult↗
Bioavailability of griseofulvin from plain tablets in Göttingen minipigs and the correlation with bioavailability in humans.
Intravenous administration of 125 mg of griseofulvin to G ottingen minipigs showed biexponential elimination of the drug from plasma, in which the half lives of the initial and terminal phases were 0.2-0.6 h and 4.3-6.6 h, respectively. The bioavailability of four griseofulvin tablets used in a human bioavailability study was investigated in the pigs and compared with the human results. The differences of Cmax and AUC between the standard product and the others were smaller in the pig than in humans, however, the correlations of Cmax and AUC between humans and minipigs were high for the four products. The differences of Tmax among the products were small, and the Tmax of the standard product was large in the pigs compared with that in humans. In addition, delayed onset of drug absorption was observed in some of the pigs. The findings suggest slow gastric emptying of the drug in the pigs. The statistically small powers for the in vivo parameters observed in the pig, seem to indicate variable absorption of the drug in the animal.
Administration, Oral↗
Effect of food on bioavailability of nalidixic acid from uncoated tablets having different dissolution rates.
The effect of food on the bioavailability of two single lots of commercial tablets and one trial tablet of nalidixic acid, varying widely in drug dissolution characteristics, was determined in healthy male subjects after oral administration. Four subjects received, in a crossover fashion, a single 250 mg dose in an uncoated tablet during periods of fasting and non-fasting. Significant differences in Cmax, Tmax and AUC0-8 were observed between the tablet having the fastest dissolution rate and the other tablets tested, when administered postprandially. Both Cmax and AUC0-8 were significantly increased after administration of the two tablets exhibiting the poorer dissolution characteristics to the non-fasting subjects. However, food was not observed to affect any of the bioavailability parameters after postprandial administration of the tablet exhibiting the fastest dissolution rate. The improvement of bioavailability of the two tablets exhibiting the poorer dissolution by food intake was ascribable to enhanced dissolution of nalidixic acid resulting from vigorous mixing and agitation in the digestive tract. It was concluded that the effect of food on the bioavailability of nalidixic acid from uncoated tablets varies with formulation factors, especially with dissolution characteristics.
Adult↗
Use of PKM-MULTI program for fitting discontinuous absorption profiles using a microcomputer.
The programs for the pharmacokinetic models with discontinuous absorption, written in BASIC, were connected to MULTI, which had been proposed for nonlinear least squares for a microcomputer by Yamaoka et al. Using this program (designated as PKM-MULTI), the same data sets previously calculated by HFCM, FITSI2 and NONLIN were fitted and the finally obtained estimates were in close agreement with those obtained previously. The plasma data of nalidixic acid were also fitted to the pharmacokinetic model with discontinuous absorption, which were suggested to be more valid compared with one compartment model with continuous absorption.
Biological Availability↗
Chronic blood vessel catheterization in Göttingen miniature pigs and application to a preliminary bioavailability study of nalidixic acid.
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Animals↗
[Power of test in bioequivalence analysis. The comparison of tests in beagle dogs and humans].
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Adult↗
Bioavailability of Nalidixic acid from uncoated tablets in humans--Part II: Bioavailability in beagles and its correlation with bioavailability in humans and in vitro dissolution rates.
The bioavailability of nalidixic acid in beagles was determined using the same tablet formulations previously tested on humans and was compared with bioavailability in humans and with in vitro dissolution rates. The beagle bioavailability test provided lower power in all of the bioavailability parameters than did the human test. Tmax of the tablets did not greatly differ in beagles, although in humans a wide variation of Tmax was seen. A linearity between Cmax and AUC0-infinity was observed in beagles, but Tmax did not show a linearity with Cmax or AUC in dogs, which is quite different from the relations observed in humans. The rank order of tablets according to Cmax was exactly the same between humans and beagles. AUC also showed the same rank order between humans and beagles except for on tablet with a poor disintegrating ability. A significant correlation between human and beagle Cmax values was obtained (r = 0.8952; p less than 0.05), but not between human and beagle AUC and Tmax values.
Animals↗
[Changes in physiochemical properties of shelved oleaginous suppository bases: the effects on indomethacin, aminopyrine and sulpyrine release rates].
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Aminopyrine↗
The bioavailability of flufenamic acid and its dissolution rate from capsules.
The bioavailabilities of five commercially available flufenamic acid (FA) capsules were studied in humans and beagle dogs. The dissolution rates of these capsules were determined by several methods. Experiments on in vitro/in vivo and humans/dogs correlations were performed to evaluate the dissolution test methods and the values of beagle dogs as models for predicting bioavailability of weak acid drugs in humans. Significant differences in the rates and extents of bioavailability of the different capsules were observed both in humans and dogs, but results in humans differed from those in dogs. The dissolution rates, determined by dissolution methods involving pretreatment with acidic solutions, correlated significantly with bioavailabilities in humans and dogs; however, those obtained by the rotating basket and paddle methods without any surface active agents did not correlate with in vivo data.
Adult↗
Bioavailability of griseofulvin from tablets in humans and the correlation with its dissolution rate.
Dissolution rates of 10 commercial microsize griseofulvin tablets and one ultramicrosize griseofulvin tablet were preliminarily determined in 18 liters of pH 7.2 phosphate buffer and in 900 ml of 40% dimethylformamide as test media. Addition of dimethylformamide affected the dissolution behavior of the formulations. The products, three microsize and one ultramicrosize, were selected for further studies on the bioavailability in humans and dissolution. Significant differences among the formulations were found in serum levels Cmax, and AUC47.5 hr, but not in AUC infinity and tmax. The maximum difference of Cmax was approximately 40%. The ultramicrosize product showed lower Cmax and serum levels at earlier sampling times than two microsize products. The dissolution rates determined under sink and nonsink conditions without pretreatment significantly correlated with the serum level at 1 hr but not with the other in vivo parameters. Only the dissolution rate determined by the sink method with pretreatment with a small quantity of water (1.0 ml) and plastic beads significantly correlated with serum levels at 3 and 5 hr, Cmax, and AUC 47.5 hr.
Biological Availability↗
Bioavailability of griseofulvin from tablets in beagle dogs and correlation with dissolution rate and bioavailability in humans.
The bioavailability of four griseofulvin tablets in beagle dogs, including an ultramicrosize tablet used previously in a human bioavailability study, was investigated on the basis of the plasma 6-demethyl-griseofulvin concentration. The relations with the in vivo findings in humans and the in vitro dissolution rates also were examined. Contrary to the lower bioavailability of the ultramicrosize formulation in humans, it provided the best bioavailability in beagles. The microsize griseofulvin formulations showed similar in vivo results to those in humans. Poor correlation of in vivo parameters between humans and beagles was attributed to the discrepancy of the availability of the ultramicrosize formulation between the two species. The dissolution rates determined by the pretreatment method using plastic beads were correlated more with the in vivo findings than those determined by the other methods. Beagles were a useful animal model for bioavailability studies of certain griseofulvin formulations but not ultramicrosize ones.
Animals↗
Effect of food on the bioavailability of griseofulvin from microsize and PEG ultramicrosize (GRIS-PEG) plain tablets.
Effect of food on the bioavailability of griseofulvin from its two plain tablets, a commercial microsize product and a PEG ultramicrosize (GRIS-PEGR) one, was investigated. The drug was dissolved at a slower rate from ultramicrosize formulation than from microsize one in 18 1 of pH 7.2 buffer but at a little faster rate in 40% dimethylformamide. When administered to fasting subjects, the microsize product showed higher serum levels and peak serum level than ultramicrosize one but the extent of the bioavailability was nearly the same. A standard breakfast enhanced the rate of absorption of the drug from both the products, especially from ultramicrosize one, and those products were equivalent in the rate and extent of bioavailability after food ingestion. The peak serum level of ultramicrosize product in nonfasting was about twice higher than that in fasting subjects. The different intensities of food effect on the bioavailabilities from two dosage forms suggest that formulation factors should be considered for the evaluation of food effect.
Adult↗
The bioavailability of flufenamic acid from aluminum flufenamate tablet and flufenamic acid capsule, and the influence of food and aluminum hydroxide gel.
The bioavailabilities of flufenamic acid (I) from a commercial aluminum flufenamate (II) tablet and I capsule were estimated by measuring urinary excretion of I and its metabolites fluorometrically. The dissolution rates of I from both dosage forms were also determined. The effects of concomitant intake of food or antacid on the bioavailabilities from the II tablet and the I capsule were investigated. The extent on I bioavailability from the II tablet was less than 30% of that from the I capsule. Dissolution tests suggested that the low bioavailability of I from II tablet resulted from the extremely slow release of I from the II complex. Intake of a standard meal retarded I absorption from I capsule, but did not affect that from the II tablet. Ingestion of dried aluminum hydroxide gel granules had little effect on I bioavailability from the I capsule.
Adult↗