Absorption of organic anions as model drugs following application to rat liver surface in-vivo

Absorption of organic anions (phenol red, bromphenol blue and bromosulphonphthalein) has been studied after their application to rat liver surface in-vivo, employing a cylindrical glass cell (i.d. 9 mm, area 0.64 cm2). Every drug appeared gradually in the blood with the peak level at about 1 h, after which its concentration declined slowly. Absorbed model drug was efficiently excreted into the bile. These observations appear to indicate the possibility of drug absorption from liver surface membrane. Absorption ratios of model drugs were estimated to be more than 59 % in 6 h. As to phenol red, its biliary recovery and metabolism ratio did not change as compared with that of i.v. administration.without figuresグラフな

Effect of albumin on the absorption of phenol red, bromphenol blue and bromosulphonphthalein as model drugs from the liver surface membrane in rats,

The effect of bovine serum albumin (BSA) on drug absorption from the liver surface in rats was examined by using three organic anions (phenol red, bromphenol blue and bromosulphonphthalein) as model drugs which have a high affinity for albumin. The binding ratio of the model drugs (3 mg/ml in phosphate buffer) to BSA varied widely at a BSA concentration of 0.1--10% (w/v). The model drugs (3 mg/ml x 0.1 ml) with or without BSA were applied to the rat liver surface in vivo employing a cylindrical glass cell (i.d. 9 mm, area 0.64 cm2). The absorption ratios of the model drugs from the rat liver surface at 6h, calculated from the amount recovered from the glass cell, decreased with an increase in BSA concentration. A similar trend was observed with biliary recovery of the model drugs. A marked reduction in the absorption ratio was seen with bromosulphonphthalein, which has the highest binding activity to BSA among the three organic anions. Accordingly, protein binding appears to be a significant factor with respect to the drug absorption from the liver surface.グラフなしwithout graph

Absorption of phenol red and bromphenol blue as model drugs from the peritoneal cavity around the liver surface in rats

The effect of the injection site on the pharmacokinetics of phenol red and bromphenol blue as model drugs after intraperitoneal (i.p.) administration into rats was examined. Their absorption rate from the peritoneal cavity was faster after i.p. administration to the liver surface (LS) than that after i.p. administration to the distal small intestine (SI), as shown by the increase in maximum concentration and decrease in mean residence time in plasma. A similar tendency was observed in the biliary excretion pattern. The enhanced absorption rate was supported by the significantly smaller amount of both drugs remaining in the peritoneal cavity at 15 min after LS administration than that after SI administration. The liver concentration of the model drugs at 15 min after LS administration was 1.5 - 2.0 times higher than that after SI administration. Accordingly, LS administration was shown to be effective with good absorbability and efficient drug delivery to the liver.without figuresグラフな

Effect of application volume and area on the absorption of phenol red as a model drug from the liver surface in rats

We examined the importance of application volume and area in the absorption of phenol red as a model drug from the rat liver surface, for pharmaceutical formulation concerning administration form. When 1 mg of phenol red was applied to the rat liver surface in-vivo using a cylindrical glass cell (i.d. 9 mm) in three volumes (0.1, 0.2 or 0.334 mL), the shape of the plasma concentration pattern differed greatly, particularly the maximum concentration. These patterns were well fitted by a two-compartment model with first-order absorption, and the obtained absorption rate constant Ka decreased inversely according to the application volume. The absorption ratio and biliary recovery of phenol red at 6 h was increased with glass cell area (i.d. 6, 9 or 14 mm; area 0.28, 0.64 or 1.54 cm2). Furthermore, the permeability coefficient Papp derived from Ka did not depend on application area, indicating no difference in absorption characteristics of liver surface. This also implies transport of a drug by a passive diffusion from the liver surface. After intraperitoneal administration to the rat liver surface for clinical application, increase in application volume resulted in the delayed disappearance of phenol red from plasma. However, the difference was not as marked as that using a glass cell. The assumption that the effective area relating to the absorption changed with the application volume enabled us to estimate Papp. Consequently, we speculate absorbability can be estimated precisely by considering application volume and area

Effect of viscous additives on drug absorption from the liver surface in rats using phenol red as a model

The purpose of this study is to obtain information that can be used to improve controlled release and residence time of drugs on the liver surface. Using carboxymethylcellulose sodium salt (CMC-Na) and polyvinyl alcohol (PVA), we examined the effect of viscous formulations on the absorption of phenol red as a model. In the presence of 3% CMC-Na or 15% PVA, the maximum plasma concentration of phenol red decreased after application to the rat liver surface using a cylindrical glass cell. The absorption ratios in 6 h calculated from the remaining amount of phenol red in the glass cell were 68.6, 60.5 and 48.7% (control: 73.1%) in the presence of 1 or 3% CMC-Na and 15% PVA, respectively. As a result of the reduction in the absorption ratio, the amount of phenol red excreted into the bile and urine in 6 h was decreased by the addition of the viscous additives. The decrease in absorption rate was characterized by a pharmacokinetic analysis of the plasma concentration profile. The change in absorption rate differed between the viscous additives, reflecting the result of the in vitro release experiment. Accordingly, the possibility that the drug absorption rate from the liver surface can be altered by viscous additives was suggested to have a promising prospect for therapeutic use

Secure and effective gene delivery system of plasmid DNA coated by polynucleotide

Polynucleotides are anionic macromolecules which are expected to transfer into the targeted cells through specific uptake mechanisms. So, we developed polynucleotides coating complexes of plasmid DNA (pDNA) and polyethylenimine (PEI) for a secure and efficient gene delivery system and evaluated their usefulness. Polyadenylic acid (polyA), polyuridylic acid (polyU), polycytidylic acid (polyC), and polyguanylic acid (polyG) were examined as the coating materials. pDNA/PEI/polyA, pDNA/PEI/polyU, and pDNA/PEI/polyC complexes formed nanoparticles with a negative surface charge although pDNA/PEI/polyG was aggregated. The pDNA/PEI/polyC complex showed high transgene efficiency in B16-F10 cells although there was little efficiency in pDNA/PEI/polyA and pDNA/PEI/polyU complexes. An inhibition study strongly indicated the specific uptake mechanism of pDNA/PEI/polyC complex. Polynucleotide coating complexes had lower cytotoxicity than pDNA/PEI complex. The pDNA/PEI/polyC complex showed high gene expression selectively in the spleen after intravenous injection into mice. The pDNA/PEI/polyC complex showed no agglutination with erythrocytes and no acute toxicity although these were observed in pDNA/PEI complex. Thus, we developed polynucleotide coating complexes as novel vectors for clinical gene therapy, and the pDNA/PEI/polyC complex as a useful candidate for a gene delivery system

Title page Communication Absorption of organic anions as model drugs following application to rat liver surface in-vivo

Abstract Absorption of organic anions (phenol red, bromphenol blue and bromosulphonphthalein) has been studied after their application to rat liver surface in-vivo, employing a cylindrical glass cell (i.d. 9 mm, area 0.64 cm2). Every drug appeared gradually in the blood with the peak level at about 1 h, after which its concentration declined slowly. Absorbed model drug was efficiently excreted into the bile. These observations appear to indicate the possibility of drug absorption from liver surface membrane. Absorption ratios of model drugs were estimated to be more than 59 % in 6 h. As to phenol red, its biliary recovery and metabolism ratio did not change as compared with that of i.v. administration