Biomedical subjects

Junzo Nakamura

Publications and source records attributed to Junzo Nakamura.

33 records · Page 2Linked to original sources

PubMed2004

Absorption of phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration.

The purpose of this study was to clarify the absorption characteristics of a drug across the mesenteric surface, which occupies a large area of absorption in the peritoneal cavity, in order to determine the drug absorption route after intraperitoneal administration. Absorption of phenolsulfonphthalein (PSP) as a model after application to the mesenteric surface was investigated in rats by employing a cylindrical diffusion cell attached to the mesentery with or without blood vessels. PSP was absorbed from the rat mesenteric surface, followed by its appearance in the plasma and bile, regardless of blood vessel existence. The absorption ratios of PSP in 6 h were calculated to be 92.1 and 83.6% from the mesenteric surface with and without blood vessels, respectively. We then employed an experimental system in which a polyethylene (PE) cap was stuck on the surface of the other side to exclude the influence of absorption of the drug from the other organ surfaces that penetrated across the mesentery. The PE cap decreased the appearance of PSP in the plasma from the mesenteric surface with blood vessels and eliminated the PSP absorption completely from the mesenteric surface without blood vessels. Accordingly, blood vessels on the mesenteric surface must actually play an important role in drug absorption, but the contribution of the mesenteric surface to drug absorption from the peritoneal cavity is unlikely to be significant because there is a small effective area of blood vessels.

Animals↗

PubMed2004

Liver site-specific gene transfer following the administration of naked plasmid DNA to the liver surface in mice.

The present study was undertaken to investigate liver site-specific gene transfer following the administration of naked plasmid DNA (pDNA) to the liver surface in mice. We examined whether genes could be delivered to the liver site specifically by utilizing the glass-made diffusion cell that is able to limit the contact dimension between the liver surface and pDNA solution administered. Gene expression was detected at the site of diffusion cell attachment (site 1) and was significantly higher than in other liver sites and tissues. Moreover, gene expression was also detected at deeper site from the liver surface (noncontact side with pDNA solution). The level of gene expression at site 1 did not change significantly with pDNA treatment for 10, 30, and 60 min. In conclusion, we demonstrated that naked pDNA administered to the liver surface in mice was taken up from its surface, and subsequently the protein encoded by pDNA could be produced site specifically.

Animals↗

PubMed2004

Pharmacokinetics of phenol red in rat models of liver damage prepared by liver targeting of carbon tetrachloride.

Animal models prepared by treatment with carbon tetrachloride (CCl(4)) have been used to examine drug disposition in hepatic disorder. However, previous studies demonstrated that systemic administration of CCl(4) impaired not only hepatic but also renal function. We recently reported that application of CCl(4) to the rat liver surface produced hepatic damage without impairing renal function. In the present study, we examined the pharmacokinetics of phenol red in our developed rat model. The rats treated with CCl(4) by liver surface application exhibited decreases in the biliary clearance of phenol red in comparison with normal rats from 0.54+/-0.03 to 0.31+/-0.06 ml/min, suggesting hepatic damage. In these rats, the renal clearance of phenol red did not decrease (0.50+/-0.16 ml/min vs. 0.46+/-0.07 ml/min in normal rats). On the other hand, oral and intraperitoneal treatments with CCl(4) reduced not only the biliary clearance of phenol red (0.34+/-0.03 ml/min in p.o. treated rats, 0.18+/-0.01 ml/min in i.p. treated rats) but also the renal clearance (0.26+/-0.05 ml/min in p.o. treated rats, 0.18+/-0.06 ml/min in i.p. treated rats) as compared with normal rats. These findings indicate that the rat model of liver damage prepared by liver surface application of CCl(4) is useful to investigate the effects of hepatic disorder on the pharmacokinetics of drugs.

Administration, Oral↗

PubMed2003

One-side-coated insert as a unique ophthalmic drug delivery system.

We newly prepared a unique one-side-coated insert that releases drug from only uncoated side. The purpose of this study is to determine whether ocular and systemic absorption of ophthalmic drug could be altered by an inserting direction of the insert in rabbit eyes. One-side-coated insert was prepared by attaching a polypropylene tape on the one side of the polymer disc of poly(2-hydroxypropyl methacrylate) (HPM) containing tilisolol as a model ophthalmic drug. The insert was applied in the lower conjunctival cul-de-sac of albino rabbits with the uncoated side facing bulbar conjunctiva/sclera (SC insert) or palpebral conjunctiva (CJ insert). At the adequate intervals, the tear fluid, plasma, aqueous humor, conjunctiva, and sclera were collected and the drug concentrations were determined by an HPLC. A release of tilisolol from the one-side-coated insert was twice slower than from the uncoated insert. Ocular application of the one-side-coated insert produced the constant concentrations of tilisolol in the tear fluid over 180 min. SC insert showed higher drug concentrations in the aqueous humor and sclera, and lower drug concentrations in the plasma and conjunctiva than CJ insert.The one-side-coated insert can alter the ocular and systemic absorption of drug by an inserting direction.

Adrenergic beta-Antagonists↗

PubMed2003

Liquid chromatography studies on the pharmacokinetics of phentermine and fenfluramine in brain and blood microdialysates after intraperitoneal administration to rats.

A highly sensitive and simple HPLC method with fluorescence detection for the determination of phentermine (Phen), fenfluramine (Fen) and norfenfluramine (Norf, the active metabolite of Fen) in rat brain and blood microdialysates has been developed. The brain and blood microdialysates were directly subjected to derivatization with 4-(4,5-diphenyl-1H-imidazol-2-yl) benzoyl chloride (DIB-Cl) in the presence of carbonate buffer (0.1 M, pH 9.0) at room temperature. The chromatographic conditions consisted of an ODS column and mobile phase composition of acetonitrile and water (65:35, v/v) with flow rate set at 1.0 ml/min. The detection was performed at excitation and emission wavelengths of 325 and 430 nm, respectively. Under these conditions, the DIB-derivatives of Phen, Fen and Norf were well separated and showed good linearities in the studied ranges (5-2000 nM for Phen and 10-2000 nM for Norf and Fen) with correlation coefficients greater than 0.999. The obtained detection limits were less than 23 fmol on column (for the three compounds) in both brain and blood microdialysates at a signal-to-noise ratio of 3 (S/N=3). The intra- and the inter-assay precisions were lower than 10%. The method coupled with microdialysis was applied for a pharmacokinetic drug-drug interaction study of Phen and Fen following individual and combined intraperitoneal administration to rats. In addition, since the role of protein binding in drug interactions can be quite involved, the method was applied for the determination of total and free Phen and Fen in rat plasma and ultrafiltrate, respectively. The results showed that Fen and/or Norf significantly altered the pharmacokinetic parameters of Phen in both blood and brain but did not alter its protein binding. On the other hand, there was no significant difference in the pharmacokinetics of Fen when administered with Phen.

Animals↗

PubMed2003

Development of the liver- and lobe-selective nonviral gene transfer following the instillation of naked plasmid DNA using catheter on the liver surface in mice.

PURPOSE: The present study has undertaken the liver- and lobe-selective nonviral gene transfer following the instillation of naked plasmid DNA (pDNA) using catheter on the liver surface in mice. METHODS: The polyethernylon catheter was inserted intraperitoneally through the abdominal wall and was retained on the surface of the liver right and left medial lobes. pDNA was administered through the catheter to the liver right and left medial lobes. RESULTS: The luciferase levels produced in the applied liver lobes at 6 h after liver surface instillation of pDNA were significantly higher than those produced in other liver lobes and other tissues assayed, and ranged from approximately 5 folds higher in other lobes to 20-30 folds higher in other tissues. Following liver surface instillation of pDNA at a time from 2 to 24 h or at a volume from 15 to 60 microl, the gene expressions of the applied liver lobes were always significantly higher than those of other liver lobes and other tissues. CONCLUSION: We have demonstrated the liver- and lobe-selective gene transfection following the instillation of naked pDNA using catheter on the liver surface in mice.

Animals↗

PubMed2003

Effect of the absorption enhancer saponin on the intrarenal distribution of 5-fluorouracil following its kidney surface application in rats.

The present study was undertaken to examine the effects of the absorption enhancer saponin on the intrarenal distribution of 5-fluorouracil (5-FU) following the kidney surface application of 5-FU in rats. We selected an experimental system utilizing a cylindrical diffusion cell attached to the kidney surface. The intrarenal concentration of 5-FU 120 min after right kidney surface application of 5-FU with saponin at concentrations of 0.25 and 1 mg/ml was modified. Among four sites in the right kidney, the concentration of 5-FU under the diffusion cell was selectively increased by saponin. These results suggest it may be possible to control the intrarenal distribution of the drug following its application with an absorption enhancer on the kidney surface.

Absorption↗

PubMed2003

Further studies on the kidney- and site-selective delivery of 5-fluorouracil following kidney surface application in rats.

The present study was undertaken to elucidate the kidney- and site-selective delivery of 5-fluorouracil (5-FU) following kidney surface application in rats. We selected an experimental system utilizing a cylindrical diffusion cell attached to the right kidney surface. After 5-FU was applied to this surface, approximately 60% was absorbed in 180 min. A semi-log plot of the remaining amount of 5-FU in the diffusion cell gave a straight line. The cumulative amount of urinary excretion of 5-FU for up to 180 min from the right ureter was significantly higher than that from the left ureter. On the other hand, the cumulative amount of urinary excretion of 5-FU from the right and left ureters after intravenous administration of the drug was similar. The 5-FU concentration at four sites in the right kidney after intravenous administration was also similar, while the drug was site-selectively delivered in the kidney after its surface application. 5-FU accumulated at the site under the diffusion cell was rapidly eliminated after its removal from the diffusion cell. From these results, we demonstrated that the absorption of 5-FU on the kidney surface in rats is explained mostly by passive diffusion. It was further elucidated that kidney surface application of this drug in rats results in its the kidney- and site-selective delivery.

Absorption↗

PubMed2003

Influence of liver disease on phenolsulfonphthalein absorption from liver surface to examine possibility of direct liver surface application for drug targeting.

We have examined the influence of liver disease on drug absorption from the liver surface membrane, regarded as the first barrier for drug targeting to the liver. The main purpose of this study is to examine the possibility of direct liver surface application as a drug targeting method. We employed rats intoxicated with carbon tetrachloride (CCl(4)) or D-galactosamine (GAL) as the liver disease model, and examined drug absorption characteristics after application to the liver surface, by utilizing a cylindrical diffusion cell. In the liver-intoxicated rats, about 90% of a low molecular weight drug, phenolsulfonphthalein (PSP), as a model was absorbed from the liver surface in 6 h, similar to the normal rats (no treatment). Although the absorption rate was increased in the CCl(4) group, whereas slightly retarded absorption was observed in GAL group, there should be no serious problem for the clinical use of liver surface application. The PSP absorption from the liver surface in the CCl(4) group was indicated to obey first-order kinetics by elimination profile from the diffusion cell. The first-order absorption rate constant K(a) values of PSP from the liver surface, obtained by a compartment model and elimination profile, were increased 1.3-fold in the CCl(4) group compared to the control. Moreover, we performed drug application to the liver surface in the peritoneal cavity to assume clinical use. The K(a) of PSP in the CCl(4) group was about 4-fold larger than in the normal group, implying the importance of estimating changes in peritoneal drug absorption as a result of liver disease. Consequently, it is expected that there will be no marked decline in the absorption rate from the liver surface in a liver disease state, leading us to apply this administration method for liver targeting.

Absorption↗

PubMed2002

Liver- and lobe-selective gene transfection following the instillation of plasmid DNA to the liver surface in mice.

The present study has undertaken the liver- and lobe-selective gene transfections following the instillation of plasmid DNA (pDNA) to the liver surface in mice. The luciferase levels produced in the applied (left) liver lobe at 6 h after liver surface instillation of pDNA were significantly higher than those produced in the other tissues assayed, and ranged from 8.5-fold higher in other liver lobes to 320-fold higher in other tissues. After small intestine surface instillation of pDNA, the gene expression was a little detected in the tissues assayed. Following liver surface instillation of pDNA at a time from 2 to 48 h or at a volume from 15 to 120 microl, the gene expressions of the applied liver lobe were always significantly higher than those of other liver lobes and other tissues. We demonstrated the novel liver- and lobe-selective gene transfection utilizing the instillation to the liver surface.

Animals↗

PubMed2002

Absorption characteristics of model compounds with different molecular weights from the serosal caecal surface in rats.

The purpose of this study was to clarify the absorption characteristics of drugs across the serosal caecal surface membrane, occupying a large absorption area in the peritoneal cavity in rats. Absorption of phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FDs) as model drugs after application to the rat serosal caecal surface was investigated using a cylindrical diffusion cell. PSP was absorbed from the rat serosal caecal surface, followed by appearance in the plasma and bile. The time course of the remaining PSP amount in the diffusion cell obeyed first-order kinetics, and the rate constant, Ka, was calculated to be 8.01 x 10(-3) min(-1). No significant difference was seen in the absorption ratio of PSP, which was approximately 90% in 6 h for three doses (0.3, 0.5 and 1 mg), suggesting linear absorption. Moreover, the absorption ratios of FDs from the rat serosal caecal surface at 3 h decreased with an increase in the molecular weight (24.7% for FD4, 12.8% for FD-10 and 3.4% for FD-40).

Absorption↗

PubMed2002

Biodistribution and pharmacokinetics of O-palmitoyl tilisolol, a lipophilic prodrug of tilisolol, after intravenous administration in rats.

The purpose of this study was to modify the biodistribution and pharmacokinetics of tilisolol, a beta-blocker, using the palmitoyl prodrug approach. After intravenous administration of tilisolol and O-palmitoyl tilisolol in rats, drug concentrations were determined in blood, bile, urine, and several tissues. The concentration-time profiles of tilisolol and O-palmitoyl tilisolol were analyzed pharmacokinetically. The blood concentrations of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10-fold higher than those of tilisolol after intravenous administration of tilisolol. The biliary excretion rates of O-palmitoyl tilisolol and tilisolol after intravenous administration of O-palmitoyl tilisolol were about 10- to 100-fold larger than those of tilisolol after intravenous administration of tilisolol. In addition, the hepatic uptake clearance of O-palmitoyl tilisolol after intravenous administration of O-palmitoyl tilisolol was 3.6-fold higher than that of tilisolol after the intravenous administration of tilisolol. In the in vitro experiments, it was demonstrated that the distribution ratios between blood cells and plasma (blood/plasma) of O-palmitoyl tilisolol and tilisolol was 95.7 and 55.5%, respectively. These findings suggest that O-palmitoyl tilisolol exists as a binding form with biological components, especially blood cells, in systemic circulation. In conclusion, the palmitoyl prodrug approach is useful as a drug delivery system to deliver the parent drug to the liver.

Animals↗

PubMed2002

A novel method for preparation of animal models of liver damage: liver targeting of carbon tetrachloride in rats.

Animal models prepared by treatment with toxic compounds such as a carbon tetrachloride have been used to examine drug disposition in hepatic diseases. However, it is possible that these compounds accumulate and cause damage to other organs as they are administered systemically. In this study, we used the liver surface application technique to deliver a toxic compound to the liver to prepare an appropriate animal model in which only the liver is significantly damaged. To restrict the absorption area in the liver, a cylindrical diffusion cell was attached to the liver surface of male Wistar rats. Twenty-four hours after direct addition of carbon tetrachloride to the diffusion cell, plasma levels of glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT), and hepatic malondialdehyde (MDA) concentration were increased, while there were no changes in plasma creatinine or renal MDA level. On the other hand, not only GOT, GPT and hepatic MDA, but also creatinine and renal MDA levels were markedly increased by p.o. and i.p. administration of carbon tetrachloride, suggesting renal damage. These results indicated that the animal models of liver damage prepared by utilizing drug delivery techniques to accumulate toxic compounds in the liver would enable us to investigate the precise effects of hepatic disorder on drug disposition.

Animals↗

PubMed2002

Kidney- and site-selective delivery of 5-fluorouracil utilizing the absorption on the kidney surface in rats.

The present study was undertaken to elucidate the kidney- and site-selective delivery of 5-fluorouracil (5-FU) utilizing the absorption on the kidney surface in rats. An experimental system utilizing a cylindrical diffusion cell attached to the right kidney surface was established. After intravenous administration of 5-FU, the concentration of 5-FU in the right and left kidneys was almost the same and was rapidly eliminated. After right kidney surface application of 5-FU, however, the concentration of 5-FU in the right kidney was significantly higher than in the left kidney and other tissues. The 5-FU concentration in four sites of the right kidney after intravenous administration was almost the same. In contrast, 5-FU was site selectively delivered in the kidney after kidney surface application. The blood concentration of 5-FU was low (<1.7 microg/ml) until 120 min after kidney surface application. The maximum blood concentration of 5-FU after kidney surface application was much lower than after intravenous administration.

Absorption↗

PubMed2002

Glycosylated cationic liposomes for cell-selective gene delivery.

Cationic liposomes have been considered as a potential nonviral vector for gene delivery because they possess low immunogenicity, unlike viral vectors. The gene transfer efficiency of cationic liposomes is lower than that ofviral vectors, but recent advances have shown that it is possible to enhance the gene expression levels of cationic liposomes. The main problem with cationic liposomes seems to be the lack of organ or cell selectivity because the lung has the highest level of gene expression after intravenous injection. Applying cell-specific targeting technology to liposomes would improve in vivo gene delivery and reduce any unexpected side effects. Both liver parenchymal and non-parenchymal cells exclusively express large numbers of high-affinity asialoglycoprotein and mannose receptors, respectively. Receptor-mediated gene delivery systems are able to introduce foreign DNA into specific cell types in vivo. However, we have confirmed that not only the nature of the ligands grafted to carriers but also the overall physicochemical properties of the complexes need to be optimized for effective cell-selective targeting of plasmid DNA. In this article, we attempt to evaluate a gene delivery system based on the physicochemical properties of plasmid DNA/glycosylated cationic complexes.

Animals↗