Naonori Kohri

Improving the Oral Bioavailability of Albendazole in Rabbits by the Solid Dispersion Technique

We have investigated the oral bioavailability of granules of albendazole, a drug used for treating echinococcosis in man, prepared by the solid dispersion technique.

Evaluation of pH-independent sustained-release granules of dipyridamole by using gastric-acidity-controlled rabbits and human subjects

The solubility of dipyridamole at pH 2.5 was about 6000-fold greater than that at pH 7.0. A commercial powder of dipyridamole showed pH-dependent dissolution. Two kinds of sustained-release granules of dipyridamole were prepared. The release rate of pH-dependent sustained-release granules was controlled by ethylcellulose (EC) and decreased with increasing medium pH. The release rate of pH-independent sustained-release granules was regulated by carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose (TC-5) and Eudragit RS100, and was not influenced by varying pH of the medium. We used gastric-acidity-controlled rabbits to evaluate the variability in absorption after oral administration of these formulations. An extremely large difference in bioavailability between the high and low gastric acidity groups was observed after oral administration of the commercial powder. There were no statistically significant differences in the values of Cmax, Tmax, AUC0–12h and MRT between the high and low gastric acidity groups after administration of pH-independent sustained-release granules, while statistically significant differences in Cmax and AUC0–12 h were found between the two groups after administration of pH-dependent sustained-release granules. Furthermore, this pH-independent sustained-release granule preparation was administered orally to human subjects and compared with the commercial powder. There was no significant difference in the AUC0–12 h between the two preparations. It was also shown that the Cmax for the granules was about 50% of that for the commercial powder and that the plasma levels after oral administration of the granules were maintained over a longer duration than those of the commercial powder. It was found that the bioavailability was not influenced by variations in gastric acidity in rabbits and high bioavailability was achieved in human subjects after oral administration of the pH-independent sustained-release granule preparation, indicating that this preparation should be a useful dosage form for the potential reduction of interindividual variabilities in absorption.

Improving the Oral Bioavailability of Sulpiride by a Gastric-retained Form in Rabbits

To improve the limited oral bioavailability of sulpiride, a gastric‐retained form was developed and evaluated using gastric‐emptying‐controlled rabbits.

Improving the Oral Bioavailability of Sulpiride by Sodium Oleate in Rabbits

To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric‐emptying‐controlled rabbits in a cross‐over manner.

Inter-subject variation in oral absorption of ketoprofen from controlled-release granules in rabbits

Abstract Three kinds of controlled-release granules of ketoprofen were prepared. The release rate of granules A was controlled by ethylcellulose (EC) and was increased with increasing the pH value in the medium. The release rates of granules B and granules C were controlled by EC, hydroxypropyl methylcellulose (HPMC) and Eudragit E100. Granules B released the drug rapidly at pH 5 and 6 in the medium, while the release from granules C was less influenced by the pH value in the medium than those from granules A and granules B. We used gastric-acidity-controlled rabbits to evaluate the variation in the absorption after oral administration of these granules. Plasma levels after administration of 3 kinds of controlled-release granules to the non-treatment group were prolonged compared with those of the commercial capsule. There were no statistically significant differences in AUC 0–24 h between each granular formulation and the commercial capsule. There were statistically significant differences in C max or T max between the high and the low gastric acidity groups after administration of granules A or granules B, while there were no statistically significant differences in C max , T max and AUC 0–24h between high and low gastric acidity groups after administration of granules C. It was indicated that pH-independent controlled-release granular formulation would be one of the useful dosage forms which could potentially reduce the inter-subject variations in absorption.

Purification by ceftibuten-affinity chromatography and the functional reconstitution of oligopeptide transporter(s) in rat intestinal brush-border membrane

The transport activity of ceftibuten, a dianionic peptide-like compound, was extracted from rat intestinal brush-border membrane by n-octylglucoside and reconstituted into asolectin liposomes by dialysis. The proteoliposomes prepared from the membrane extract showed an inward H+-gradient-dependent uptake of ceftibuten and glycylsarcosine. Ceftibuten-immobilized affinity chromatography of the membrane extract permitted the isolation of two polypeptides (apparent molecular mass of 117 and 127 kDa) that can recognize the dianionic peptide structure of ceftibuten. Proteoliposomes prepared from reconstituting the isolated proteins into asolectin vesicles showed an overshooting uptake of ceftibuten in the presence of an inwardly directed H+ gradient, and this uptake could be inhibited by L-valyl-L-proline. N-glycanase digestion of the isolated proteins, 117 and 127 kDa, trimmed them into 78 and 120 kDa products, respectively. The protein core size of the smaller protein was in agreement with the calculated molecular mass of approximately 79 kDa for the rat PepT1 transporter obtained by other investigators.

Serum alpha-1-acid glycoprotein and protein binding of disopyramide in patients with congestive heart failure

Congestive heart failure is the end stage of cardiac disease and the haemodynamics in patients become very abnormal. Drug effects may also become modified and some changes have been shown in their pharmacokinetics [1, 2]. The intensity of the pharmacological effects of many drugs is determined by the serum concentration, especially the free concentration. Alpha-l-acid glycoprotein (AAG) binds many basic and neutral drugs. A A G levels were reported to change as a result of physiological and pathophysiological conditions [3-5]. There do not appear to have been reports of the level of A A G in patients with chronic heart failure. Disopyramide binds to A A G and it is used in the treatment of cardiac failure as an antiarrhythmic agent [6]. The serum A A G level and protein binding of disopyramide in vitro at the therapeutic concentrations found in patients with chronic heart failure have been studied. All patients were hospitalized for congenital heart disease, valvular heart disease or congestive cardiomyopathy. All were receiving diuretics and digitalis on admission. A few were also taking captopril. Patients with renal insufficiency (serum creatinine > 1.5 mg. dl1) and those taking drugs reported to bind to A A G were excluded [3, 4]. Sera from 4 men and 4 women of NYHA Class IV were studied on admission and 2 weeks later. A A G concentration was measured using a plate immunoassay (Medical & Biological Lab., Nagoya, Japan). Albumin was measured using an AutoAnalyzer. To examine the free fraction of disopyramide in vitro, each serum sample in which the drug level was adjusted to 5 gg. m1-1, was ultrafiltered through a Centriflow C3 LGC apparatus (Millipore Co., Betford, MA. U. S. A.). The disopyramide concentration was measured by HPLC. In short, 0.1 ml ultrafiltrate was added to 0.1 ml internal standard (nicardipine) and was then injected into the HPLC. The column was a HITACHI 3053 (ODS-18) and it was held at 55 °C. The eluent was 0.2 M acetic ammonium methanol (30 : 70) and the flow rate was 0.7 ml/min. UV detection wave length was 270 nm. Statistical analysis used Students paired t test. The results are summarised in Table 1. The medicines being taken did not change after admission except for increased doses of furosemide. The NYHA class fell from IV to III after treatment. The A A G concentration declined significantly and there was a significant increase in the free fraction of disopyramide (P < 0.05). The albumin concentration did not change. The A A G concentration may change from a normal of 0.5 mg/ml to 3.0 mg/ml in disease [5]. The A A G level here was shown to be increased in patients with severe heart failure. After partial recovery, the A A G concentration fell. Various reasons have been suggested for such a change [5], but the mechanism remains unknown. Sudden death is a significant hazard amongst patients with congestive heart failure. Disopyramide is used for cardiac arrhythmias. Its therapeutic concentration is narrow range 2 ~tg-m1-1 to 5 pg. mlt) and toxic effects occur above 8 gg-m1-1 [6]. Disopyramide is more than 90% bound to A A G and less than 10 % to albumin [6]. Changing the A A G level therefore has significance for this drug and others bound to AAG. The free fraction of disopyramide in vitro showed wide interindividual variation in patients with heart failure. The interindividual variation and A A G concentrationdependent changes in the free drug fraction complicate interpretation of total drug concentration. Therapeutic dose monitoring may be limited when only the total serum

Purification and liposomal reconstitution of the oligopeptide transport activity in rat renal cortex using ceftibuten-affinity chromatography

The carrier protein(s) responsible for the transport of ceftibuten, a peptide-like dianionic cefem, in rat renal brush-border membrane were solubilized and purified by a ceftibuten-ligand specific affinity chromatography technique. The proteoliposomes reconstituted from the solubilized brush-border membrane proteins by dialysis had H+-sensitive uptake of ceftibuten and trans-stimulative effect by cephalexin. A specific uptake activity for ceftibuten was found in the 3.5 M-eluted fraction but not the flowthrough and the 0.5 M-eluted fraction of the affinity chromatography. Analyzing this active fraction by SDS/PAGE after reconstituting into liposomes gave two major proteins (approx. molecular masses of 130 and 107 kDa). The purification protocol presented in this study permitted an efficient isolation of the carrier proteins responsible for the transport of ceftibuten and other peptide-like compounds.