Effect of viscous additives on the absorption and hepatic disposition of 5-fluorouracil (5-FU) after application to liver surface in rats

Objectives The aim was to study the effect of viscous additives on the absorption and hepatic disposition of 5‐fluorouracil (5‐FU) after application to the liver surface in rats. Methods 5‐FU solution with or without viscous additives was applied to the rat liver surface with a cylindrical diffusion cell. Then, blood and the remaining solution in the diffusion cell were collected at selected times, followed by excision of the liver. The excised liver was divided into three sites and assayed for 5‐FU content. Key findings The absorption rate of 5‐FU from the liver surface was decreased in the presence of carboxymethylcellulose sodium (CMC‐Na) and polyvinyl alcohol (PVA) as compared with the control. The k_a values of PVA 15% and CMC‐Na 1% were reduced to about 80 and 67% of the control. The maximum plasma concentration of 5‐FU was decreased by incorporation of viscous additives. The 5‐FU concentration at the diffusion cell attachment site of the liver (site 1) plateaued at 180 min in the absence of viscous additives. On the other hand, the concentration of 5‐FU at site 1 increased in a time‐dependent manner until 360 min in the presence of viscous additives. Conclusion Viscous additives might be useful for retaining drugs at their application site and controlling the rate of absorption from the liver surface.     

Regional Delivery of Model Compounds and 5-Fluorouracil to the Liver by Their Application to the Liver Surface in Rats: Its Implication for Clinical Use

Purpose The purpose of this study was to examine drug distribution in the liver after drug application to the rat liver surface.Methods Phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextran (MW 4400, FD-4) as model compounds or 5-fluorouracil (5-FU) was applied to the rat liver surface by employing a cylindrical diffusion cell (i.d. 9 mm, 0.64 cm²). Then, blood and the remaining solution in the diffusion cell were collected at selected times, followed by excision of the liver. The excised liver was divided into three sites: the region under the diffusion cell attachment site (site 1), the applied lobe except for site 1 (site 2), and non-applied lobes (site 3).Results In the case of i.v. administration, there were no differences in PSP concentrations among the three sites of the rat liver, and the concentrations rapidly decreased. On the other hand, the PSP concentration in site 1 after application to the rat liver surface was considerably higher than in site 2 and site 3. In addition, the area under the curve (AUC) value (AUC_site1), calculated from the PSP concentration profile in site 1, was about 10 times larger than that in site 3. A similar trend of regional delivery advantage by liver surface application was observed in the case of the macromolecule model FD-4, with a marked AUC_site1 of about 5 times larger than the other two sites. Moreover, we clarified that the anticancer drug 5-FU preferentially distributed in site 1 after application to the rat liver surface.Conclusion These results demonstrate the possibility of regional delivery of drugs to the liver by application to the liver surface.     

Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects

The present study was undertaken to elucidate the absorption and distribution characteristics of 5-fluorouracil (5-FU) after its application to the liver surface in rats to examine the possibility of reducing the systemic side effects of this agent. 5-FU was applied to the surface of the liver by employing a cylindrical diffusion cell. Approximately 69% of the dose was absorbed in 360 min. The time course of the change in the amount of 5-FU remaining in the diffusion cell obeyed first-order kinetics. Also, a linear relationship was observed between the apparent permeability coefficient, P app, and the reciprocal of the square root of the molecular weight of several compounds including 5-FU. The estimated P app value of 5-FU was in good agreement with the experimental value. The plasma concentration of 5-FU was low (<1.2 microg/ml) until 360 min after the application. Following i.v. administration, 5-FU was rapidly eliminated from the plasma and could not be detected at 120 min. In the analysis of tissue distribution, the liver was divided into three sites; the region under the diffusion cell attachment site (site 1), the treated lobe excluding site 1 (site 2), and untreated lobes (site 3). After being administered i.v., 5-FU mainly distributed in the kidney, and the concentration in the liver was significantly lower than that in kidney, spleen, or heart. After its application to the liver surface, however, 5-FU preferentially distributed at site 1, and was not detected at the other sites or in other tissues. Thus, these results suggested the possibility of a reduction in the systemic side effect of 5-FU on its application to the liver surface.     

Stomach- and site-selective delivery of 5-fluorouracil following its application on the gastric serosal surface in rats

The present study was undertaken to elucidate the stomach- and site-selective delivery of 5-fluorouracil (5-FU) following its application on the gastric serosal surface in rats. An experimental system utilizing a cylindrical diffusion cell attached to the gastric serosal surface was established. To evaluate the gastric distribution of 5-FU, the stomach was separated into the site under the diffusion cell (site 1) and the site not under the diffusion cell (site 2). Furthermore, the mucosal side at site 1 was separated from the serosal side. After intravenous and oral administration of 5-FU, the 5-FU concentrations at sites 1 and 2 until 240 min were similar. After gastric serosal surface application of 5-FU, however, the concentration of 5-FU at site 1 until 240 min was approximately 10-fold higher than that at site 2, and was sustained. Furthermore, the 5-FU concentration on the mucosal side at site 1 and the serosal side at site 1 were comparable after gastric serosal surface application. The blood concentration of 5-FU was low (<4.4 microg/ml) until 240 min after gastric serosal surface application. The maximum blood concentration of 5-FU after gastric serosal surface application was significantly lower than after intravenous administration. Thus, the stomach- and site-selective delivery system following application on the gastric serosal surface could be applied with anticancer drugs for the treatment of gastric cancer.     

Effect of dimethylnitrosamine‐induced liver dysfunction on the pharmacokinetics of 5‐fluorouracil after administration of S‐1, an antitumour drug,to rats

Objectives The anti‐tumour agent S‐1 comprises tegafur (a prodrug of 5‐fluorouracil; 5‐FU), gimeracil (2‐chloro‐2,4‐dihydroxypyridine (CDHP); a competitive inhibitor of 5‐FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5‐FU after administration of S‐1 to rats was investigated. Methods S‐1 (5 mg/kg) was administered intravenously and orally to rats with DMN‐induced liver dysfunction. Plasma concentrations of S‐1 components and 5‐FU were measured by HPLC and LC/MS‐MS. Blood tests and in‐vitro enzymatic investigations were also conducted. Key findings DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5‐FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S‐1, the blood concentration‐time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half‐life of tegafur was significantly prolonged. The maximum plasma concentration (C_max) of 5‐FU was significantly reduced and the area under the blood concentration‐time curve (AUC) was reduced by 22%. Following oral administration, the C_max of tegafur, 5‐FU and CDHP were significantly decreased and half‐lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5‐FU (13.6% reduction). Conclusions The pharmacokinetic profiles of tegafur, 5‐FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5‐FU. However, hepatic dysfunction had less of an effect on the AUC of 5‐FU, which correlates with anti‐tumour effect, after the oral administration of S‐1.     

Poly(amidoamine) dendrimers as skin penetration enhancers: Influence of charge, generation, and concentration

The study investigates the influence of surface charge, generation and concentration of poly(amidoamine) (PAMAM) dendrimers on skin permeation of a model hydrophilic drug, 5-fluorouracil (5FU). Permeation studies were performed using excised porcine skin in a Franz diffusion cell. Saturated concentration of 5FU in isopropyl myristate was applied on the skin after pretreatment with dendrimers and (14)C labeled 5FU was analyzed using a liquid scintillation counter. The influence of dendrimer surface charge (G4-NH(2), G3.5-COOH, and G4-OH), generations (G2-G6-NH(2)) and concentration (0.1-10 mM of G4-NH(2)) on skin permeation of 5FU were studied. The enhancement in drug permeability coefficient (K(p)) was in the following decreasing order G4-NH(2) > G4-OH > G3.5-COOH. Dendrimer increased the skin permeation by increasing the skin partitioning of 5FU. Transepidermal water loss, skin resistance measurements and ATR-FTIR studies revealed that cationic dendrimers act by interacting with the skin lipid bilayers. Increase in G4-NH(2) concentration did not proportionally increase the skin permeation of 5FU. The 5FU K(p) was inversely related to the molecular weight of the dendrimer. G2-NH(2) dendrimer reduced skin resistance to a greater extent than higher generation dendrimers. Overall, the study showed that lower generation cationic dendrimer is more effective in enhancing the skin permeation of hydrophilic drugs.     

Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

The objective of this work was to develop a liver‐specific antihepato carcinoma agent. A series of 5‐fluorouracil / cholic acid conjugates (5‐FU‐cholic acid conjugates) were prepared and tested for their chemical characteristics and bio‐distribution properties. The in‐vitro stability trial showed 5‐FU‐cholic acid conjugates could be completely hydrolyzed by heating at 70°C in an acidic solution, pH = 1, for 5 min. The fast and complete hydrolysis of these compounds could be compatible with a fast separation and analysis method to shorten the analysis time. The decomposition speeds of the 5‐FU‐cholic acid conjugates in different organs of mice at several time points after oral administration were evaluated by measuring the concentrations of regenerated 5‐FU in organ tissue. The results were compared with those of the controls, which was a group of mice orally taking 5‐FU. The concentrations of 5‐FU in mice liver tissue were remarkably increased after oral administration of the prodrugs, and were much larger than if only orally administered 5‐FU. The results suggested the feasibility to improve therapeutic efficiency of liver targeting treatments by using cholic acid as the vector of drugs.     

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.     

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.     

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.     

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.     

Hepatic fibrosis does not affect the pharmacokinetics of 5-fluorouracil in rats

In the case of cancer chemotherapy for hepatocellular carcinoma, 5‐fluorouracil (5‐FU) is used widely, and has typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. 5‐Fluorouracil is eliminated primarily by the liver, and so its use in patients with hepatic disease can be difficult. This study investigated the effect of hepatic fibrosis on the pharmacokinetics of 5‐FU in rats. Experimental hepatic fibrosis was induced by carbon tetrachloride treatment. 5‐Fluorouracil was infused for 15 min into the hepatic artery or the saphenous vein of the rats at a dose of 1.25 mg/kg. There were no significant differences in the plasma concentration and AUC of 5‐FU between hepatic disease rats and their controls after both intravenous and intraarterial injection. This result is probably attributed to the fact that there were no significant differences in hepatic blood flow and dihydropyrimidine dehydrogenase (DPD; an initial and rate‐limiting enzyme in 5‐FU catabolism) activity between hepatic disease rats and their controls, because the total clearance of 5‐FU after intravenous and intraarterial administration is mainly limited by hepatic blood flow and DPD activity, respectively. In conclusion, the pharmacokinetics of 5‐FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs. Copyright © 2010 John Wiley & Sons, Ltd.     

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.     

Application of hydrotropy to transdermal formulations: hydrotropic solubilization of polyol fatty acid monoesters in water and enhancement effect on skin permeation of 5-FU

Objectives A hydrotropic formulation containing a percutaneous enhancer was developed for the transdermal formulation of a water‐soluble drug and the solubilizing mechanisms of a percutaneous enhancer in water by a hydrotropic agent were investigated. The enhancement effect was also compared with the hydrotropic formulation and the other formulations using ethanol, propylene glycol or mixed micelles. Methods Sodium salicylate (SA) and sodium benzoate (BA) were selected as hydrotropic agents, and polyol fatty acid ester (POFE) and 5‐fluorouracil (5‐FU) were selected as a percutaneous enhancer and a water‐soluble drug, respectively. Near‐infrared (NIR) spectrophotometric and ¹H NMR spectroscopic studies were carried out to investigate the solubilizing mechanisms. The mean particle size in the hydrotropic formulation was measured. The in‐vitro skin permeation of 5‐FU and the accumulation in the skin of propylene glycol monocaprylate (PGMC), one of the monoesters of POFE, from the hydrotropic formulation or the other formulations were investigated by using Franz‐type diffusion cell. Key findings The presence of SA and BA had a visible effect on the O–H stretching band of water in the NIR region. The surface tension of SA and BA aqueous solutions was found to decrease with an increase in SA or BA concentration. Although SA interacted with PGMC in the presence of water, it did not interact with PGMC in the absence of water. Mean particle size in a solution consisting of 5% (v/v) PGMC and 30% SA aqueous solution was approximately 14 nm. ¹H NMR spectroscopic studies indicated that the hydrotropic salts formed aggregates with which PGMC interacted from the outside. The hydrotropic formulation prepared in this study enhanced skin permeation of 5‐FU when compared with the other formulations. Conclusions SA and BA solubilized monoesters of POFE in water, and SA interacted with PGMC in water. The hydrotropic formulation prepared in this study significantly enhanced skin permeation of 5‐FU compared with the other formulations. The results suggest that a hydrotropic formulation containing PGMC may be a useful transdermal formulation for water‐soluble drugs.     

The differential effects of prazosin and hydralazine on sympathoadrenal activity in conscious rats

The ability of the vasodilator hydralazine and the alpha 1-adrenoceptor antagonist prazosin to increase sympathoadrenal outflow was compared by measuring plasma norepinephrine and epinephrine concentrations, norepinephrine clearance and norepinephrine spillover rate into plasma in conscious Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Even though the vasodepressor effect of 1 mg/kg (i.p.) of prazosin (-23 mm Hg) was significantly less than that caused by 1 mg/kg (i.p.) of hydralazine (-31 mm Hg) in normotensive rats, the increases in plasma norepinephrine concentration and norepinephrine spillover rate were significantly larger in prazosin-treated rats. In conscious SHR, 0.5 mg/kg (i.p.) of prazosin and 0.3 mg/kg (i.p.) of hydralazine lowered blood pressure to the same extent (-22 mm Hg), but prazosin again produced significantly larger increases in plasma norepinephrine concentration and norepinephrine spillover rate. Neither prazosin nor hydralazine affected norepinephrine clearance, and only prazosin elicited a significant rise in plasma epinephrine concentration. This differential effect of prazosin and hydralazine on sympathoadrenal activity is best explained by the differing effects of these drugs on venous return and thus the afferent activity of the cardiopulmonary baroreceptors.     

Entrapment of 5-fluorouracil into PLGA matrices using supercritical antisolvent processes

Objectives Two different supercritical antisolvent processes were performed to co‐precipitate 5‐fluorouracil (5‐FU) and poly(lactide‐co‐glycolide) simultaneously. 5‐FU is a hydrophilic antitumor agent, and is more effective when administered at a lower dose for a longer period of time. Methods Controlled‐release polymeric systems of 5‐FU were produced, and morphology, thermal behavior, in‐vitro release and cytotoxicity of microparticles were analysed. Key findings Dissolution studies showed that 33% of drug was released in 21 days, which represents a long‐lasting profile. To evaluate the efficacy of the released drug on cancer cells, the MTT assay cytotoxicity test was performed using human lung carcinoma A549 cell lines. There was no significant difference between the cell inhibition rates of the released drug and unprocessed 5‐FU at the same drug concentration level. IC50 values were 69.12 mg/ml for unprocessed 5‐FU and 68.71 mg/ml for the released drug. Conclusions Application of supercritical processing for co‐precipitation of 5‐FU and PLGA provided mild and non‐aqueous conditions, so the hydrophilic drug incorporated in the polymer had good stability during the process.     

Effects of cadralazine on contractions induced by norepinephrine, serotonin, angiotensin II and K+ in rabbit aortic and renal arterial strips

Antagonistic effects of the new antihypertensive agent cadralazine (ethyl(+/-)-6-[ethyl(2-hydroxypropyl)-amino]-3-pyridazinecarbazate ) and its metabolite ISF-2405 [+/-)-6-[ethyl(2-hydroxypropyl)amino]-3-hydrazinopyridazine) on norepinephrine (NE), 5-hydroxytryptamine (serotonin), angiotensin II (angio II) and KCl induced contractions of rabbit abdominal aortic and renal arterial strips were compared with those of hydralazine. Substantially, cadralazine does not exert any effect on cumulative dose-response curves of these agonists in both vessel preparations even with the highest concentration of 10(-4) mol/l. ISF-2405 and hydralazine at concentrations of 10(-5) and 10(-6) mol/l showed non-competitive antagonism, depending not only on the dose but also on the length of the pretreatment time, on NE-induced contractions of abdominal aorta and renal artery. The two drugs attained maximal pD2 values with 60 min pretreatment without showing significant difference between the two vessel preparations, suggesting that the inhibitory effect of these drugs does not show vascular bed-related difference against NE-induced contractions. 60 min pretreatment with 10(-6) and 10(-5) mol/l of ISF-2405 and hydralazine also manifested non-competitive antagonism on contractile responses to serotonin, angio II, and K+ for both compounds. The degree of antagonistic effects of ISF-2405 and hydralazine on these agonists is similar, the order being angio II greater than serotonin greater than NE greater than K+. These results suggest that ISF-2405 and hydralazine exert direct vasodilating effects by the same mode of action at a site other than receptors against Ca2+ mobilization.     

Apoptosis,Dysbiosis and Expression of Inflammatory Cytokines are Sequential Events in the Development of 5‐Fluorouracil‐Induced Intestinal Mucositis in Mice

The chemotherapeutic agent 5‐fluorouracil (5‐FU) causes intestinal mucositis with severe diarrhoea, but the pathogenesis is not fully understood. In this study, we investigated the pathogenic effects of 5‐FU in mice, focusing on apoptosis, enterobacteria and inflammatory cytokines. Repeated administration of 5‐FU caused severe intestinal mucositis on day 6, accompanied by diarrhoea and body‐weight loss. TNF‐α expression increased 1 day after exposure to the drug, and spiked a second time on day 4, at which point myeloperoxidase activity and IL‐1β expression also increased. Apoptotic cells were observed in intestinal crypts only on day 1. 5‐FU also induced dysbiosis, notably decreasing the abundance of intestinal Firmicutes while increasing the abundance of Bacteroidetes and Verrucomicrobia. Twice‐daily co‐administration of oral antibiotics significantly reduced the severity of intestinal mucositis and dysbiosis, and blocked the increase in myeloperoxidase activity and cytokine expression on day 6, without affecting apoptosis and TNF‐α up‐regulation on day 1. In cultured colonic epithelial cells, exposure to 5‐FU also up‐regulated TNF‐α expression. Collectively, the data suggest that crypt apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of intestinal mucositis after exposure to 5‐FU. In particular, 5‐FU appears to directly induce apoptosis via TNF‐α and to suppress intestinal cell proliferation, thereby resulting in degradation of the epithelial barrier, as well as in secondary inflammation mediated by inflammatory cytokines.     

Development of drug delivery system based on a new administration route for targeting to the specific region in the liver

Development of drug delivery systems to achieve site-specific delivery or prolonged retention in the circulation has attracted attention, because new types of drugs are expected to be created with advances in life science and biotechnology such as the Human Genome Project. We have tried to develop a new administration route for drug targeting to the liver, since drug administration by the intravenous and oral routes makes it difficult to achieve a local site of action in the liver. Although direct application to the liver surface should result in local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore we analyzed the absorption mechanism of several organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in vivo, employing a cylindrical diffusion cell. Every compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. A specific transport system might not be involved in the absorption process from the liver surface, because the effect of dose and transport inhibitors on the absorption was not recognized. In addition, molecular weight was found to be a determining factor in absorption from the liver surface. The targeting efficacy was considerably enhanced by application to the liver surface, as compared with intravenous administration. Moreover, we have identified important physicochemical and pharmaceutical factors determining the absorption rate of a drug from the liver surface for clinical use. Consequently, drug application to the liver surface could improve availability in the desired site of a new drug such as bioactive compounds and genomic medicines, by combination with appropriate chemical and pharmaceutical formulation modifications.     

Absorption Characteristics of Dextrans with Different Molecular Weights from the Liver Surface Membrane in Rats: Implications for Targeting to the Liver

Abstract

We examined the importance of molecular weight on the absorption from the liver surface in rats using fluorescein isothiocyanate-dextrans (FDs) with molecular weights of 4,400 (FD-4), 9,300 (FD-10), 40,500 (FD-40) or 69,000 (FD-70). After application of FDs (5 mg) to the rat liver surface employing a cylindrical glass cell (i.d. 9 mm), each FD appeared gradually in the plasma, and the in vivo behavior was explained by two-compartment model with first-order absorption. The absorption ratios of FDs from the rat liver surface at 6 h, calculated from the amount recovered from the glass cell, decreased with an increase in the molecular weight (44.5% for FD-4, 29.3% for FD-10, 5.1% for FD-40 and 2.2% for FD-70). A linear relationship was observed between the absorption rate constant and the reciprocal value with square root of molecular weight of the model compounds. The limit of absorption from the rat liver surface was extrapolated to be at a molecular weight of 70,000. Furthermore, absorbed FDs were accumulated in the liver, as high liver/plasma concentration ratio as compared with that of i.v. administration.

We clarified the molecular weight dependence of drug absorption from the liver surface in rats. Moreover, the liver surface application appeared to be a promising route with enhancing the efficacy of drug targeting to the liver.