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Junzo Nakamura - One of the best experts on this subject based on the ideXlab platform.
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absorption of Phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Koyo Nishida, Seiichi Nose, Akiko Kuma, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Junzo NakamuraAbstract: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.
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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
Pharmaceutical Research, 2005Co-Authors: Koyo Nishida, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Rie Fujiwara, Yukinobu Kodama, Shintaro Fumoto, Junzo NakamuraAbstract: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 cm^2). 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.
Koyo Nishida - One of the best experts on this subject based on the ideXlab platform.
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absorption of Phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Koyo Nishida, Seiichi Nose, Akiko Kuma, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Junzo NakamuraAbstract: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.
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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
Pharmaceutical Research, 2005Co-Authors: Koyo Nishida, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Rie Fujiwara, Yukinobu Kodama, Shintaro Fumoto, Junzo NakamuraAbstract: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 cm^2). 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.
Nakamura Junzo - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of changes in hepatic disposition of Phenolsulfonphthalein, indocyanine green and fluorescein isothiocyanate-dextran at low temperatures using a rat liver perfusion system
'Wiley', 2012Co-Authors: Miyamoto Hirotaka, Fumoto Shintaro, Sasaki Hitoshi, Nakamura Junzo, Miyake Hideaki, Yoshikawa Naoki, Hirata Haruna, Ohwaki Yuichi, Nishida KoyoAbstract:Objectives The aim of this study was to determine the factor changing the hepatic disposition of a drug during hypothermia using a rat liver perfusion system. Methods The livers of male Wistar rats were perfused at 37, 32 or 28°C in the single-pass mode. Venous outflow dilution patterns and biliary excretion rate patterns of Phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, MW 4400) after the injection of a bolus into the perfused rat liver were analysed based on statistical moment theory. Key findings The first-pass extraction ratio (E h) of PSP was significantly decreased at 32 and 28°C compared with 37°C. The biliary recovery of PSP and its conjugate was decreased and the biliary excretion was kept at a high concentration and was prolonged by low perfusion temperatures. ICG was almost extracted by a single-pass through the liver even at 32 and 28°C. The biliary recovery of ICG was significantly decreased at low temperature. Although the distribution volume of FD-4 as a vascular reference was not changed by perfusion temperature, the E h of FD-4 was decreased at 28°C although not markedly. Conclusion The change in hepatic disposition of a drug at low perfusion temperatures differed according to disposition processes under hypothermia
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Change in Pharmacokinetics of Model Compounds with Different Elimination Processes in Rats during Hypothermia
'Pharmaceutical Society of Japan', 2007Co-Authors: Nishida Koyo, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Nakamura Junzo, Miyake Hideaki, Okazaki Madoka, Sakamoto Ryuichi, Inaoka Natsuko, Kakumoto MikioAbstract:We compared the pharmacokinetics of model compounds with different elimination processes between hypothermic and normothermic rats, to obtain basic information concerning drug therapy during hypothermia. Male Wistar rats were anesthetized with sodium pentobarbital and kept at temperatures of 37 °C (normothermic group) by heat lamp, and 32 °C or 28 °C (hypothermic group) by external cooling. We chose Phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, Mw 4400) as model compounds to determine changes in clearance pathways during hypothermia therapy. The plasma concentrations of PSP as biliary, urinary and metabolic elimination type were increased significantly in the hypothermic group (32 °C, 28 °C) after i.v. administration at a dose of 1 mg, compared to the normothermic group (37 °C). Each PSP clearance (bile, urine and metabolites) in the hypothermic group was decreased, suggesting an influence of hypothermia on the active elimination process. The decreasing tendency was marked at a temperature of 28 °C. Moreover, the plasma concentrations of ICG as the biliary excretion type after i.v. administration to the hypothermic rats at a dose of 1 mg were higher with more than 50% decrease in the total body clearance compared to normothermic rats. On the other hand, there was almost no difference in the i.v. pharmacokinetics of FD-4 as the urinary excretion type between 37 °C and 32 °C. However, renal clearance of FD-4 was significantly decreased at a temperature of 28 °C. Accordingly, the change in pharmacokinetics of a drug in the hypothermic group could differ with the elimination processes
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Absorption characteristics of model compounds from the small intestinal serosal surface and a comparison with other organ surfaces
Pharmaceutical Press, 2005Co-Authors: Nishida Koyo, Kuma Akiko, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Nakamura JunzoAbstract:We examined the absorption of Phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FD-4, MW 4,400; FD-10, MW 9,500; FD-40, MW 40,500) as model compounds through the small intestinal serosal surface. After application to the rat small intestinal serosal surface using a cylindrical diffusion cell, each compound was absorbed at different rates. The absorption ratios in 6 h after PSP, FD-4, FD-10 and FD-40 application were calculated to be 89.2, 34.6, 14.9 and 2.1 % of dose, respectively. Elimination profiles of PSP, FD-4 and FD-10 from the small intestinal serosal surface obeyed first-order kinetics. Moreover, we calculated the apparent permeability coefficient Papp for comparison to other organ surfaces. The kidney had the highest absorption efficiency, as shown by having more than 1.5 times significantly higher Papp values of PSP, FD-4 and FD-10. Similar to the other organ surfaces, a correlation was observed between the Papp of small intestine and the molecular weight of these hydrophilic compounds. In addition, the small intestine is likely to contribute largely to hydrophilic compounds absorption from the peritoneal cavity, judging from absorption clearance CLa calculated by utilizing the peritoneal organ surface area
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Delivery advantage to the unilateral kidney by direct drug application to the kidney surface in rats and pharmacokinetic verification based on a physiological model
'Informa UK Limited', 2005Co-Authors: Nishida Koyo, Kuma Akiko, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Mukai Takahiro, Kamenosono Manabu, Nakamura JunzoAbstract:The objective of this study was to evaluate the drug delivery advantage to the unilateral kidney by direct drug application to the rat kidney surface based on a physiological pharmacokinetic model. Under anesthesia, a cylindrical diffusion cell (i.d. 6 mm, area 0.28 cm(2)) was attached to the right kidney surface in rats. Phenolsulfonphthalein (PSP), an organic anion chosen as a model compound, was added into the diffusion cell. The free PSP concentration in the right (applied) kidney after application to the right kidney surface at a dose of 1 mg was significantly higher than that of the left (non-applied) kidney until 60 min after application. Similarly, the urinary excretion rate of free PSP from the applied kidney was much faster than that from the non-applied kidney, with a 2.6 times larger excreted amount in 240 min. These results imply the possibility that a considerable drug delivery advantage to the unilateral kidney could be obtained after direct absorption from the kidney surface. This tendency was also observed at the other application doses of 0.3 and 1.5 mg. On the other hand, fluorescein isothiocyanate dextran (Mw 4400, FD-4) was equally excreted into the urine from each kidney and the renal concentrations in the applied and non-applied kidneys were almost the same, possibly due to the involvement of passive transport for the absorbed FD-4, i.e. glomerular filtration. The computer simulations of free PSP concentrations in the plasma and each kidney based on a physiological model after kidney surface application were consistent with the respective experimental data. Moreover, the delivery advantage of kidney surface application of PSP was verified by its comparison with other routes such as i.v. and i.a. administrations
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Absorption of Phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration
Pharmaceutical Press, 2004Co-Authors: Nishida Koyo, Kuma Akiko, Nakashima Mikiro, Sasaki Hitoshi, Nose Seiichi, Mukai Takahiro, Nakamura JunzoAbstract:The purpose of this study is to clarify 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 by sticking a polyethylene cap (PE cap) 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-sticking 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 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 due to there being a small effective area of blood vessels
Nishida Koyo - One of the best experts on this subject based on the ideXlab platform.
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Novel Diagnostic Method of Peritoneal Injury Using Dual Macromolecular Markers
'Pharmaceutical Society of Japan', 2014Co-Authors: Hirata Haruna, Fumoto Shintaro, Nakashima Mikiro, Miyamoto Hirotaka, Shimokawa Kenta, Nakayama Morio, Nishida KoyoAbstract:Long-term peritoneal dialysis (PD) frequently produces morphological and functional changes of the peritoneum, which makes continuation of PD difficult. Moreover, the progression of peritoneal injury causes complications and poor prognosis. Since therapeutic treatments for peritoneal injury during PD have yet to be established, it is important to diagnose peritoneal injury as early as possible. The aim of this study was to develop a method of monitoring peritoneal function to diagnose peritoneal injury. Model rats of peritoneal injury were prepared by intraperitoneal injection of methylglyoxal (MGO) for five consecutive days. Then, marker substances of various molecular weights (Phenolsulfonphthalein, fluorescein isothiocyanate-dextran (FD)-10, FD-40, FD-70, FD-2000 or tetramethylrhodamine-dextran (RD)-10) were injected into the peritoneal cavity. At 120 min after injection, the remaining amounts of all marker substances were significantly decreased in the MGO-treated rats compared with those in the vehicle-treated rats. Molecular weight dependence of the peritoneal permeability was observed. A substance with a molecular weight of approximately 10000 was found to be suitable to diagnose peritoneal injury. Moreover, coadministration of RD-10 with FD-2000 enabled us to monitor enhanced peritoneal permeability and the transfer of water simultaneously, without the recovery of whole PD fluid, even in the case of different ultrafiltration volumes. We demonstrated the usefulness of administering substances to evaluate peritoneal permeability and the transfer of water simultaneously to diagnose peritoneal injury. This study should be valuable for safe and effective PD
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Evaluation of changes in hepatic disposition of Phenolsulfonphthalein, indocyanine green and fluorescein isothiocyanate-dextran at low temperatures using a rat liver perfusion system
'Wiley', 2012Co-Authors: Miyamoto Hirotaka, Fumoto Shintaro, Sasaki Hitoshi, Nakamura Junzo, Miyake Hideaki, Yoshikawa Naoki, Hirata Haruna, Ohwaki Yuichi, Nishida KoyoAbstract:Objectives The aim of this study was to determine the factor changing the hepatic disposition of a drug during hypothermia using a rat liver perfusion system. Methods The livers of male Wistar rats were perfused at 37, 32 or 28°C in the single-pass mode. Venous outflow dilution patterns and biliary excretion rate patterns of Phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, MW 4400) after the injection of a bolus into the perfused rat liver were analysed based on statistical moment theory. Key findings The first-pass extraction ratio (E h) of PSP was significantly decreased at 32 and 28°C compared with 37°C. The biliary recovery of PSP and its conjugate was decreased and the biliary excretion was kept at a high concentration and was prolonged by low perfusion temperatures. ICG was almost extracted by a single-pass through the liver even at 32 and 28°C. The biliary recovery of ICG was significantly decreased at low temperature. Although the distribution volume of FD-4 as a vascular reference was not changed by perfusion temperature, the E h of FD-4 was decreased at 28°C although not markedly. Conclusion The change in hepatic disposition of a drug at low perfusion temperatures differed according to disposition processes under hypothermia
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Change in Pharmacokinetics of Model Compounds with Different Elimination Processes in Rats during Hypothermia
'Pharmaceutical Society of Japan', 2007Co-Authors: Nishida Koyo, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Nakamura Junzo, Miyake Hideaki, Okazaki Madoka, Sakamoto Ryuichi, Inaoka Natsuko, Kakumoto MikioAbstract:We compared the pharmacokinetics of model compounds with different elimination processes between hypothermic and normothermic rats, to obtain basic information concerning drug therapy during hypothermia. Male Wistar rats were anesthetized with sodium pentobarbital and kept at temperatures of 37 °C (normothermic group) by heat lamp, and 32 °C or 28 °C (hypothermic group) by external cooling. We chose Phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, Mw 4400) as model compounds to determine changes in clearance pathways during hypothermia therapy. The plasma concentrations of PSP as biliary, urinary and metabolic elimination type were increased significantly in the hypothermic group (32 °C, 28 °C) after i.v. administration at a dose of 1 mg, compared to the normothermic group (37 °C). Each PSP clearance (bile, urine and metabolites) in the hypothermic group was decreased, suggesting an influence of hypothermia on the active elimination process. The decreasing tendency was marked at a temperature of 28 °C. Moreover, the plasma concentrations of ICG as the biliary excretion type after i.v. administration to the hypothermic rats at a dose of 1 mg were higher with more than 50% decrease in the total body clearance compared to normothermic rats. On the other hand, there was almost no difference in the i.v. pharmacokinetics of FD-4 as the urinary excretion type between 37 °C and 32 °C. However, renal clearance of FD-4 was significantly decreased at a temperature of 28 °C. Accordingly, the change in pharmacokinetics of a drug in the hypothermic group could differ with the elimination processes
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Absorption characteristics of model compounds from the small intestinal serosal surface and a comparison with other organ surfaces
Pharmaceutical Press, 2005Co-Authors: Nishida Koyo, Kuma Akiko, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Nakamura JunzoAbstract:We examined the absorption of Phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FD-4, MW 4,400; FD-10, MW 9,500; FD-40, MW 40,500) as model compounds through the small intestinal serosal surface. After application to the rat small intestinal serosal surface using a cylindrical diffusion cell, each compound was absorbed at different rates. The absorption ratios in 6 h after PSP, FD-4, FD-10 and FD-40 application were calculated to be 89.2, 34.6, 14.9 and 2.1 % of dose, respectively. Elimination profiles of PSP, FD-4 and FD-10 from the small intestinal serosal surface obeyed first-order kinetics. Moreover, we calculated the apparent permeability coefficient Papp for comparison to other organ surfaces. The kidney had the highest absorption efficiency, as shown by having more than 1.5 times significantly higher Papp values of PSP, FD-4 and FD-10. Similar to the other organ surfaces, a correlation was observed between the Papp of small intestine and the molecular weight of these hydrophilic compounds. In addition, the small intestine is likely to contribute largely to hydrophilic compounds absorption from the peritoneal cavity, judging from absorption clearance CLa calculated by utilizing the peritoneal organ surface area
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Delivery advantage to the unilateral kidney by direct drug application to the kidney surface in rats and pharmacokinetic verification based on a physiological model
'Informa UK Limited', 2005Co-Authors: Nishida Koyo, Kuma Akiko, Fumoto Shintaro, Nakashima Mikiro, Sasaki Hitoshi, Mukai Takahiro, Kamenosono Manabu, Nakamura JunzoAbstract:The objective of this study was to evaluate the drug delivery advantage to the unilateral kidney by direct drug application to the rat kidney surface based on a physiological pharmacokinetic model. Under anesthesia, a cylindrical diffusion cell (i.d. 6 mm, area 0.28 cm(2)) was attached to the right kidney surface in rats. Phenolsulfonphthalein (PSP), an organic anion chosen as a model compound, was added into the diffusion cell. The free PSP concentration in the right (applied) kidney after application to the right kidney surface at a dose of 1 mg was significantly higher than that of the left (non-applied) kidney until 60 min after application. Similarly, the urinary excretion rate of free PSP from the applied kidney was much faster than that from the non-applied kidney, with a 2.6 times larger excreted amount in 240 min. These results imply the possibility that a considerable drug delivery advantage to the unilateral kidney could be obtained after direct absorption from the kidney surface. This tendency was also observed at the other application doses of 0.3 and 1.5 mg. On the other hand, fluorescein isothiocyanate dextran (Mw 4400, FD-4) was equally excreted into the urine from each kidney and the renal concentrations in the applied and non-applied kidneys were almost the same, possibly due to the involvement of passive transport for the absorbed FD-4, i.e. glomerular filtration. The computer simulations of free PSP concentrations in the plasma and each kidney based on a physiological model after kidney surface application were consistent with the respective experimental data. Moreover, the delivery advantage of kidney surface application of PSP was verified by its comparison with other routes such as i.v. and i.a. administrations
Takahiro Mukai - One of the best experts on this subject based on the ideXlab platform.
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absorption of Phenolsulfonphthalein as a model across the mesenteric surface in rats to determine the drug absorption route after intraperitoneal administration
Journal of Pharmacy and Pharmacology, 2010Co-Authors: Koyo Nishida, Seiichi Nose, Akiko Kuma, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Junzo NakamuraAbstract: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.
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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
Pharmaceutical Research, 2005Co-Authors: Koyo Nishida, Takahiro Mukai, Mikiro Nakashima, Hitoshi Sasaki, Rie Fujiwara, Yukinobu Kodama, Shintaro Fumoto, Junzo NakamuraAbstract: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 cm^2). 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.