Food effect on meal administration time of pharmacokinetic profile of cilostazol, a BCS class II drug.

Cilostazol (CLZ) is categorized as a biopharmaceutical classification system (BCS) class II drug. CLZ suspensions of jet-milled particles were orally administered to beagle dogs in fasted and fed states, for which food was given 0.5 h before the experiment.The mean highest concentration of CLZ (Cmax) and the area under the serum concentration-time curve (AUCt) fed/fasted ratios were 2.90 and 2.85, respectively, indicating a large and variable food effect. Additionally, CLZ was administered to the same dogs at 2 and 4 h after food or 0.5 h before food. The serum concentrations of CLZ were similar when dosed 0.5 and 2 h after food; however, they were significantly lower when dosed 4 h after food but still greater compared with the fasted state.Furthermore, the ratio of fed/fasted in AUCt was better correlated than that in Cmax. Additionally, the serum concentrations were similar to the fasted states when CLZ was dosed 0.5 h before food.Therefore, the results of this study showed that the serum concentration-time profile of CLZ was significantly affected by the timing of food administration, and that a good correlation was observed between food administration time and the Cmax and AUCt fed/fasted ratios.

Determination of SDS using fluorescent γ-cyclodextrin based on TICT in aqueous solution.

Fluorescent γ-cyclodextrin derivatives, modified using N-phenyl-x-anthracenecarboxamido (ACs; x = 9, 1), were synthesized and investigated using fluorescence and UV-vis spectroscopy. Fluorescence enhancements of ACs were observed up to 12-fold by the addition of sodium dodecyl sulfate (SDS) below the critical micellar concentration (CMC). In the presence of a nonionic surfactant, such as Triton X-100, fluorescence spectra were scarcely changed. The fluorescence selectivity between SDS and Triton X-100 was clarified from the different spectral behaviors by circular dichroism and (1)H NMR spectroscopies.

TritonX-100 selective chemosensor based on beta-cyclodextrin modified by anthracene derivative.

Beta-cyclodextrin (CD) modified by 2-(9-anthracenecarboxamido)phenyl group (Ant-CD) was synthesized and their complexation behavior was investigated by UV and fluorescence spectroscopy. Fluorescence intensity of Ant-CD was dramatically enhanced ca. 10-fold by the addition of TritonX-100 (TX-100) in water below the critical micelle concentration. Ant-CD also showed ca. 4-fold fluorescence increasing in the addition of analogous materials, n-octylbenzenesulfonate in water. These results indicate that Ant-CD can act as a highly sensitive and selective chemosensor for TX-100. Ant-CD and TX-100 formed a pseudorotaxane supramolecular complex. This result was supported by (1)H-(1)H NOESY NMR measurement.

New "off-on" responsible fluoroionophores for alkaline earth metal ions based on benzo-15-crown-5 bearing 9-phenanthreneacetamide.

The photochemical behaviors of a series of 9-phenanthreneacetamide (PA) derivatives were investigated using UV, fluorescence, and (1)H-NMR spectroscopy in acetonitrile solutions. To apply the electron transfer (ET) action of PA as a detecting moiety of chemosensors, 4'-(9-phenanthreneacetamido)-benzo-15-crown-5 (1) and 3'-methyl-4'-(9-phenanthreneacetamido)-benzo-15-crown-5 (2) were synthesized. After metal ion complex formation, the fluorescence intensity increased with increased concentration of the guest alkaline earth metal ions. The photochemical responses of the fluorescence intensity, as defined by the fluorescence intensity ratio (I(max)/I(0)) between free and complex of 1 for Ca(2+), was determined to be 4.76. However, the addition of guest ions in a solution of 2 greatly enhanced the fluorescence intensity of 2. The I(max)/I(0) of 2 was 16.6 for Ca(2+). The efficiency of ET of PA can be tuned by adding an electron-donating group onto a suitable position; fluorescent 2 was able to read out metal ions as an "Off-On" fluorescence signal.

Optimization of suppository preparation containing sodium laurate and taurine that can safely improve rectal absorption of rebamipide.

We previously reported that the fatty base suppository containing sodium laurate (C12) and taurine (Tau) (C12-Tau suppository) could enhance the colonic absorption of rebamipide, a poorly water-soluble and poorly absorbable drug, without any serious mucosal damages in rats. In the preset study, in order to make C12-Tau suppositories available for practical use, the scaling-up studies of animal and formulation size were performed, compared with the suppositories containing sodium caprate (C10) (C10 suppository) at the same amounts as those contained in the commercial products. Twenty-mg C12 improved the dissolution of rebamipide from suppository remarkably and the addition of 30-mg Tau only slightly decreased the dissolution rate. The absorption of rebamipide from rabbit rectum was more markedly improved by suppositories containing C12 than C10 suppositories. Although Tau tended to attenuate the absorption-enhancing effect of C12, several C12-Tau suppositories kept high bioavailability values, which were much higher than control. Histopathological studies showed that Tau exerted the cytoprotective action and that C12-Tau suppositories were better than C10 suppositories in safety. Considering the balance between efficacy and safety, the suppository containing 10- or 20-mg C12 with 30-mg Tau is better than C10 suppositories as commercial products and could be promising for practical use in human.

Development of suppository formulation safely improving rectal absorption of rebamipide, a poorly absorbable drug, by utilizing sodium laurate and taurine.

To develop the safe formulation that can safely improve bioavailability of poorly absorbable drugs and that is practically available, we prepared the suppositories of rebamipide, a poorly soluble and poorly absorbable antiulcer drug, by employing the combinatorial use of sodium laurate (C12), an absorption enhancer, with taurine (Tau) or L-glutamine (L-Gln), an adjuvant exerting the cytoprotective action. Although the dissolution of rebamipide from fatty base (FB) suppository prepared using Witepsol H-15 was very slow, it was remarkably improved by the addition of C12 and L-Gln or Tau into the suppository. On the other hand, the dissolution of rebamipide from water-soluble base (WB) suppository prepared using polyethylene glycol was very rapid and the addition of adjuvants did not influence its dissolution so much. Rectal absorption of rebamipide examined in rats was remarkably improved by FB suppository containing C12 or both C12 and Tau, while the enhancing effect of C12 was relatively small in the case of WB suppositories. Biochemical and histopathological studies have confirmed that FB suppository containing both C12 and Tau or L-Gln did not cause any serious local damage, while FB suppository containing C12 only caused the erosion and shrinkage for a lot of rectal epithelial cells. In conclusion, FB suppository employing the combinatorial use of C12 with Tau could be a promising formulation that is effective and safe enough for poorly absorbable drugs to be practically administered.

Combinatorial use of sodium laurate with taurine or L-glutamine enhances colonic absorption of rebamipide, poorly absorbable antiulcer drug, without any serious histopathological mucosal damages.

We previously reported that the combinatorial use of sodium laurate (C12) with several amino acids such as taurine (Tau) and L-glutamine (L-Gln) enhanced the colonic absorption of phenol red with attenuating the local toxicity caused by C12. However, even these amino acids could not protect epithelial cells from being damaged if the mucosal damage got worse to the coagulation necrosis by an excessive dose of C12. Comparing C12 with sodium caprate (C10), used in drug products marketed, 100 micromol C10 was needed to exert the similar absorption-enhancement of rebamipide, a poorly absorbable antiulcer drug, to that by 10 micromol C12, and 100 micromol C10 was obviously more toxic to the mucosa than 10 micromol C12. The combinatorial use of C12 with Tau or L-Gln enhanced the colonic absorption of rebamipide four to nine times larger in AUC than the control. Histopathologic studies clearly showed that Tau and L-Gln exerted the cytoprotective action on epithelial cells suffering from slight damages such as shrinkage and exfoliation, more articulately at 6 h than at 1.5 h after dosing. In conclusion, the combinatorial use of C12 with Tau or L-Gln could lead to a novel formulation improving the bioavailability of poorly absorbable drugs without any serious local damages.

Effect of co-administration of cationic macromolecules on the in vivo disposition and in situ renal disposition characteristics of rhIL-11.

The effects of co-administration of cationic proteins on the in vivo disposition characteristics of recombinant human interleukin-11 (rhIL-11) in mice and on the renal disposition in the perfused rat kidney were investigated. Following a bolus intravenous injection of 10 microg/kg (111)In-labeled rhIL-11, along with cationic proteins at high dose (50 mg/kg), the plasma clearance of (111)In-labeled rhIL-11 was significantly decreased mainly due to a reduction in the hepatic clearance of (111)In-labeled rhIL-11. The effect on the renal clearance was relatively small, suggesting that the kidney has a high clearance capacity. The urinary excretion ratio increased by a factor of 2 or 4 with co-administration, suggesting that the cationic character of rhIL-11is involved in tubular re-absorption. An in situ renal disposition study supports these postulations. Thus, the renal and hepatic disposition of rhIL-11 is based on nonspecific cationic interaction. These data suggest that an efficient delivery system for this cytokine would require the reduction of electrostatic interaction of this molecule with these tissues in order to reduce the plasma clearance rate. These findings provide useful information for the construction of an rhIL-11 delivery system.