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Hajime Takikawa

Publications and source records attributed to Hajime Takikawa.

At least 19 recordsLinked to original sources
PubMed2006

Effect of cyclosporin A on the biliary excretion of cholephilic compounds in rats.

Cyclosporin A (CsA) is known to cause cholestasis. CsA is reported to competitively inhibit the transport of the substrates of the bile salt export pump (Bsep), multidrug resistance protein 2 (Mrp2) and P-glycoprotein (P-gp) in the canalicular membrane vesicles. However, the inhibitory effect of CsA on various substrates of the canalicular ATP-dependent transporters in vivo is unknown. Therefore, in the present study, the acute effect of CsA on the biliary excretion of the substrates of Bsep, Mrp2 and P-gp was examined under the same condition. Ten minutes after the intravenous administration of CsA (25mg/kg), the biliary excretion of various bile acids and organic anions and cations was studied. CsA decreased the biliary excretion of tracer amounts of taurocholate, leukotriene C(4), estradiol-17beta-glucuronide, pravastatin, vinblastine and erythromycin. In contrast, the biliary excretion of high doses of taurocholate and sulfobromophthalein was only slightly or not inhibited by CsA. In conclusion, CsA may competitively inhibit biliary excretion of substrates of Bsep, Mrp2 and P-gp also in vivo, and CsA is considered to inhibit bile acid-dependent bile flow by the competitive inhibition of the canalicular transport of bile acids by Bsep.

Journal Article↗
PubMed2006

Biliary excretion of sulfated bile acids and organic anions in zone 1- and zone 3-injured rats.

BACKGROUND AND AIMS: There are several reports on the biliary excretion of bile acids and organic anions in zone 1- and zone 3-injured rat liver, but the results are controversial. In order to dissolve the discrepancy between previous works about the role of hepatic zonation on the hepatic handling of the substrates of multidrug resistance protein 2, the biliary excretion of sulfated bile acids, pravastatin and phenolphthalein glucuronide was studied in zone 1- and zone 3-injured rats. METHODS: Zone 1 and zone 3 injury were caused by allyl alcohol and bromobenzene, respectively. Bile acid sulfates, pravastatin and phenolphthalein glucuronide were administered i.v. to bile duct-cannulated rats, and their biliary excretion was studied. RESULTS: The biliary excretion of a tracer dose of taurolithocholate-3-sulfate and its excretory maximum were unchanged in zone 1 injury, but were diminished in zone 3 injury, whereas the biliary excretion of taurochenodeoxycholate-3-sulfate was unchanged in zone 1 and zone 3 injury. The biliary excretion of pravastatin and phenolphthalein glucuronide was markedly decreased only in zone 3 injury, whereas the excretory maximum of phenolphthalein glucuronide was decreased in both zone 1 and zone 3 injury. CONCLUSIONS: These findings indicate that zone 3 is important for the biliary excretion of substrates of multidrug resistance protein 2.

ATP-Binding Cassette Transporters↗
PubMed2005

Efficacy of ribavirin monotherapy following combination therapy with interferon alfa-2b and ribavirin for patients with chronic hepatitis C.

Reappearance of HCV-RNA followed by exacerbation of biochemical parameters after combination therapy consisting of interferon and ribavirin is an obstacle to achieve sustained response and improve long-term prognosis. We hypothesed that ribavirin monotherapy after 6 months of combination therapy may improve sustained viral and biochemical responses, and conducted a prospective, randomized and controlled study. Thirty-eight patients with chronic hepatitis C treated with combination therapy for 6 months and had no detectable serum HCV-RNA were enrolled, and allocated into two arms. Group I (n=19) was continuously administered oral ribavirin for additional 6 months, and group II (n=19) was followed up without any further treatment. At the end of trial, HCV-RNA negativity was 11/19 (58%) in group I, and 6/19 (32%) in group II (p=0.191). Multivariant analysis demonstrated that ribavirin monotherapy was not a predictor for the eradication of HCV-RNA. In cases without sustained viral responses, serum ALT levels at baseline and the end of 48 weeks' trial were 54.6 and 44.4 in group I (p=0.237), and significant reduction with ribavirin monotherapy was not observed. In conclusion, ribavirin monotherapy following combination therapy fails to improve sustained viral response as well as biochemical response.

Journal Article↗
PubMed2005

Biliary excretion of olmesartan, an anigotensin II receptor antagonist, in the rat.

BACKGROUND AND AIM: Olmesartan (RNH-6270) is a newly developed anigotensin II receptor antagonist, and has been reported to be excreted into feces. To examine the mechanism of the biliary excretion of olmesartan, we studied its biliary excretion in rats. METHODS: The biliary excretion of olmesartan in Eisai hyperbilirubinemic rats (EHBR), a multidrug resistance protein 2-deficient rat, was compared with control rats, and the effect of organic anions and cation and bile acids on the biliary excretion of olmesartan was studied in control rats. RESULTS: The biliary excretion of olmesartan was markedly delayed in EHBR. The biliary excretion of olmesartan was inhibited by sulfobromophthalein, cefpiramide and pravastatin, but was not inhibited by taurocholate or tauroursodeoxycholate. Vinblastine inhibited and phenothiazine treatment increased the biliary excretion of olmesartan. CONCLUSIONS: These findings suggest that olmesartan is excreted into the bile mainly by multidrug resistance protein 2 and partly by P-glycoprotein.

ATP-Binding Cassette Transporters↗
PubMed2005

Biliary excretion of taurocholate, organic anions and vinblastine in rats with alpha-naphthylisothiocyanate-induced cholestasis.

BACKGROUND AND AIMS: alpha-Naphthylisothiocyanate (ANIT) is known to cause cholestasis due to injury of the bile duct epithelial cells. The aim of the present study was to examine the effect of a single dose of ANIT on the biliary excretion of various cholephilic compounds and on the amount of canalicular transporters. METHODS: Twenty-four hours after the oral administration of ANIT (100 mg/kg), the biliary excretion of taurocholate, leukotriene C(4), pravastatin and vinblastine was studied. The protein levels of the bile salt export pump and multidrug resistance protein 2 and the immunostaining of multidrug resistance protein 2 in the liver were also examined. RESULTS: The ANIT treatment markedly decreased the biliary excretion of tracer amounts of taurocholate, leukotriene C(4), pravastatin and vinblastine. The biliary excretory maximum of taurocholate was also markedly decreased after ANIT treatment. The ANIT treatment had no effect on the protein levels of bile salt export pump and multidrug resistance protein 2 and the immunostaining of multidrug resistance protein 2 in the liver. CONCLUSIONS: These findings support canalicular transporters having little effect on the marked impairment of biliary excretion of cholephilic compounds in ANIT-induced cholestasis.

1-Naphthylisothiocyanate↗
PubMed2004

Comparison of urinary excretion of pravastatin and temocapril in bile duct-ligated rats and Eisai hyperbilirubinemic rats (EHBR).

BACKGROUND/PURPOSE: In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion. METHODS: In the present study, the urinary excretion of pravastatin and temocapril was studied in bile-duct-ligated rats (BDLR) for 3 days and in Eisai hyperbilirubinemic rats (EHBR). After urinary bladder cannulation, radiolabeled pravastatin and temocapril were injected intravenously. Urine samples were collected every 1 h for 4 h, and the radioactivity was counted. RESULTS: Urinary excretion of pravastatin was markedly increased in BDLR (85.9% of the dose after 4 h) and moderately increased in EHBR (35.9% of the dose after 4 h) compared with that in control rats (5.5% of the dose after 4 h). Similar but less prominent differences were observed with temocapril after it was administered (50.7%, 38.2%, and 22.0% of the dose after 4 h in BDLR, EHBR, and the controls, respectively). CONCLUSIONS: The absence of biliary excretion of anionic drugs was compensated for by urinary excretion in BDLR and EHBR, and the compensation was more efficient with pravastatin than with temocapril. In patients with complete bile duct obstruction, the only pathway for the elimination of cholephilic compounds is through the urine. Although changes in various transporters in the liver and kidney in cholestasis have been elucidated, little is known about how effectively the elimination of these compounds is compensated for by urinary excretion.

Animals↗
PubMed2004

Biliary excretion of bile acids and organic anions in rats with dichloroethylene-induced bile canalicular injury.

BACKGROUND: Hepatocytes in zone 1 of the hepatic lobule play a role in the uptake and biliary excretion of bile acids and organic anions under physiological conditions, and hepatocytes in zone 3 may play a role only when there is a high-dose load. To further elucidate the role of hepatic zonation in the hepatic handling of bile acids and organic anions, the biliary excretion of these compounds was studied in rats with dichloroethylene (DCE)-induced selective zone 3 bile canalicular injury. METHODS: Biliary excretion of various bile acids and organic anions was studied in rats 1 h after oral administration of DCE (5 mg/100 g). The effect of DCE on the immunostaining of multidrug resistance protein 2 (Mrp2; an important canalicular organic anion transporter) in the liver was also examined. RESULTS: The biliary excretory maximum of taurocholate and tauroursodeoxycholate was decreased in DCE-treated rats, whereas the biliary excretion of taurolithocholate-sulfate and phenolphthalein-glucuronide was unchanged in DCE-treated rats, and DCE treatment decreased the biliary excretion of sulfobromophthalein and pravastatin. DCE decreased Mrp2 staining in the canalicular membrane of zone 3 hepatocytes on immunohistochemistry. CONCLUSIONS: These findings indicate that canalicular transport in zone 3 hepatocytes is important in the biliary excretion of bile acids and organic anions, when they are administered at high doses.

ATP-Binding Cassette Transporters↗
PubMed2004

Analysis of 388 cases of primary sclerosing cholangitis in Japan; Presence of a subgroup without pancreatic involvement in older patients.

We analyzed 388 cases of primary sclerosing cholangitis (PSC) in Japan, according to a questionnaire sent to gastroenterologists. There was male predominance (59%), and interestingly there were two peaks in the age distribution as seen in the previous study. Jaundice and itching, major symptoms in PSC patients included in the diagnostic criteria, were observed only 28 and 16%, respectively. Alkaline phosphatase level was less than twofold of the upper limit of the normal range in 35%. In this regard, the diagnostic criteria in 2003 from Mayo Clinic, including cholestatic symptoms and two to three-fold increases in serum alkaline phosphatase, should be modified in Japan. Inflammatory bowel diseases were complicated in 37%, and autoimmune pancreatitis (AIP) in 7.2%. PSC cases with inflammatory bowel diseases were younger than the average, creating the first peak in the age distribution, and have similar characteristics compared to patients with PSC in foreign countries. By contrast, those with AIP, who were more than 50 years old, responded well to corticosteroid therapy. In addition, even after the exclusion of cases of sclerosing cholangitis complicated with AIP, the second peak in the age distribution was clearly evident. Therefore, we conclude that PSC patients without apparent involvement of the pancreas are present in the older patients and seem to be specific in Japan.

Journal Article↗
PubMed2004

Biliary excretion of azelnidipine, a calcium antagonist, in rats.

BACKGROUND AND AIMS: Azelnidipine (CS-905) is a novel dihydropyridine calcium antagonist that is known to be excreted in feces. To examine the mechanism of biliary excretion of azelnidipine, the authors studied its biliary excretion in Eisai hyperbilirubinuria rats (EHBR), multidrug resistance protein (Mrp)2-deficient rats, and the effect of cholephilic compounds on the biliary excretion of azelnidipine in rats. METHODS: Radiolabeled azelnidipine was intravenously administered to EHBR and control rats, and the biliary excretion of radiolabeled metabolites was studied. Furthermore, the effect of sulfobromophthalein, taurocholate and vinblastine on the biliary excretion of azelnidipine metabolites was also studied in control rats. RESULTS: The biliary excretion of azelnidipine metabolites was delayed in EHBR. The biliary excretion of azelnidipine metabolites was inhibited by sulfobromophthalein and vinblastine, but was not inhibited by taurocholate or phenothiazine pretreatment. CONCLUSION: These findings suggest that the metabolites of azelnidipine are excreted into the bile partly by Mrp2 and P-glycoprotein.

Animals↗
PubMed2004

Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats.

BACKGROUND AND AIM: Colchicine, an inhibitor of intracellular vesicular transport, has been reported to inhibit the biliary excretion of bile acids and organic anions, but the previous findings are controversial. In order to systematically evaluate the effect of colchicine on the biliary excretion of cholephilic compounds, we studied the effect of colchicine on the biliary excretion of substrates of various canalicular transporters, which were administered at or above the excretory maximum in rats. METHODS: Substrates of various canalicular adenosine triphosphate-binding-cassette transporters were infused at or above the rate of maximum excretion into rats, and the effect of colchicine (0.2 mg/100 g), which was intraperitoneally injected 3 h before, on the biliary excretion was studied. Furthermore, the effect of tauroursodeoxycholate (TUDC) co-infusion on the biliary excretion of taurocholate (TC) after colchicine treatment was also studied. RESULTS: The biliary excretion of TC and cholate administered at the rate of 1 micro mol/min/100 g was markedly inhibited by colchicine, whereas that of TUDC was not inhibited even with the infusion rate of 2 micro mol/min/100 g. TUDC co-infusion at the rate of 1 micro mol/min/100 g increased the biliary excretion of TC (1 micro mol/min/100 g), which was decreased by the colchicine pretreatment. The biliary excretory maximum of taurolithocholate-sulfate and sulfobromophthalein, substrates of the multidrug resistance protein 2, of erythromycin, a substrate of the P-glycoprotein, and of indocyanine green were not affected by colchicine. CONCLUSIONS: The different excretory maximums of TC and TUDC and the different effect of colchicine on the excretion of these bile acids are considered to be a result of different regulatory mechanisms of vesicular targeting of the bile salt export pump to the canalicular membrane by these bile acid conjugates. The vesicular targeting of the multidrug resistance protein 2 and the P-glycoprotein to the canalicular membrane is considered to be colchicine insensitive in the absence of bile acid coadministration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Urinary excretion of bile acids in bile duct-ligated rats.

BACKGROUND: In patients with complete bile duct obstruction, the only pathway of bile acid elimination is through the urine. However, the urinary excretion of various bile acid conjugates in the presence of bile duct obstruction has not been clarified. Given this factor, the urinary excretion of various bile acids was compared in rats that were bile duct-ligated for 3 days. METHODS: After urinary bladder cannulation, radiolabeled bile acids were intravenously injected, and urine samples were collected every 2 h for 6 h, and radioactivity was counted. RESULTS: Urinary excretion (cumulative percent dose during 6 h) of taurocholate and cholate was similar (19.3% and 16.8%). Urinary excretion of tauroursodeoxycholate, lithocholate, and taurolithocholate-sulfate was less effective (12.7%, 9.8% and 2.1%, respectively). Cholate was mostly conjugated with taurine, and lithocholate was mostly conjugated with taurine and further hydroxylated. CONCLUSIONS: These results indicate that unconjugated bile acids were taken up by the liver and excreted into the blood after further biotransformation even under conditions of complete bile duct obstruction. Although bile acid sulfates are the major bile acids in the urine of patients with obstructive jaundice, monohydroxylated bile acids are considered not to be so effectively excreted into the urine, even with conjugation with taurine and sulfate, in rats.

Animals↗
PubMed2003

Giant epithelial cyst of the accessory spleen.

Splenic cysts are uncommon, and cysts derived from the accessory spleen are rare. We report a case of a huge splenic cyst derived from the accessory spleen in the omentum, concomitant with multiple epithelial cysts of the primary spleen. Both serum and cystic fluid concentrations of carbohydrate antigen (CA)19-9 were markedly elevated. A huge monolocular cyst occupied the entire abdomen. A total of 71 of aspirated cystic fluid was turbid and yellowish-brown. The cyst wall, which consisted of CA19-9-positive squamous epithelium, contained approximately 2 x 3 x 1cm of splenic tissue. There was a separate multicystic 16 x 8-cm spleen in the normal position. The CA19-9 serum level returned to normal postoperatively.

Adult↗
PubMed2003

Effect of dexamethasone on biliary excretion of bile acids and organic anions in rats.

Multidrug resistance protein 2 (Mrp2) is an important transporter for biliary excretion of organic anions, and is reported to be up-regulated by dexamethasone. In the present study, effect of dexamethazone (1 mg/kg) on biliary excretion of bile acids and organic anions was studied in rats. After bile duct cannulation, bile acids and organic anions were intravenously administered, and their biliary excretion was studied. Biliary excretion of tracer doses of taurocholate and taurolithocholate-sulfate was unchanged with dexamethasone. Dexamethasone increased the excretory maximum of taurolithocholate-sulfate and sulfobromophthalein to 1.8 and 1.5 times, respectively, whereas it did not change the excretory maximum of phenolphthalein-glucuronide and taurocholate. Dexamethasone also increased biliary glutathione excretion. These results obtained by in vivo studies can be explained by the up-regulation of Mrp2, which had been reported in in vitro studies.

Journal Article↗