Biomedical subjects

R Totsuka

Publications and source records attributed to R Totsuka.

9 recordsLinked to original sources

PubMed2002

Decreased activity of hepatic P-glycoprotein in the isolated perfused liver of the adjuvant arthritis rat.

1. We investigated the hepatobiliary transport of doxorubicin in the isolated perfused liver prepared from the adjuvant arthritis rat, an animal model for rheumatoid arthritis, to examine the hepatic P-glycoprotein activity in the adjuvant arthritis rat. 2. Liver was isolated from the normal and the adjuvant arthritis rat and perfused for 60 min with recirculating buffer and the perfusate and bile samples were collected at timed interval. 3. The elimination of doxorubicin in the adjuvant arthritis rat tended to be reduced, but it was not significantly different from the normal rat. Biliary clearance (CL(bile)) in the normal rat was 1.93 +/- 0.48 ml min(-1), whereas, CL(bile) in the adjuvant arthritis rat was significantly decreased to 0.40 +/- 0.13 ml min(-1). 4. CL(bile) was markedly decreased to about 0.15 ml min(-1) in the presence of 100 microM verapamil in both types of rat. Methotrexate treatment had no effect on CL(bile) in both the normal and adjuvant arthritis rat (2.18 +/- 0.22 and 0.47 +/- 0.22 ml min(-1), respectively). 5. The results suggest that the hepatic P-glycoprotein activity was markedly decreased in the adjuvant arthritis rat and the effect of methotrexate on the hepatic P-glycoprotein activity did not corresponded to its anti-inflammatory effect.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Differences in pharmacokinetics and hepatobiliary transport of a novel anti-inflammatory agent between normal and adjuvant arthritis rats.

1. The pharmacokinetics, particularly the hepatobiliary transport of T-5557 ((3-methyl-2-oxo-piperadin-3-yl)-acetic acid N'-(3-thieophen-2-yl-8-methoxy-quinazolin-1-yl)-hydrazide), a novel anti-inflammatory agent, has been examined in normal and adjuvant arthritis (AA) rats. 2. Following oral administration of T-5557, the absolute bioavailability in AA rats was increased by sixfold compared with normal rats. The extent of binding T-5557 to plasma proteins obtained from AA rats was markedly greater than in normal rats (97.0 versus 88.2%). The biliary clearance in AA rats was significantly lower than that in normal rats (1.186 versus 5.621 ml min(-1) kg(-1)), and lower intrinsic biliary clearance was also observed in AA rats (40.33 versus 69.83 ml min(-1) kg(-1)). 3. Concomitant administration of T-5557 with quinidine, a potent P-glycoprotein inhibitor, to normal rats caused a significant decrease in the biliary clearance of T-5557 by 37.9%. Moreover, the transport of T-5557 for the apical-to-basal compartment in a Caco-2 cells' monolayer was fourfold lower than that for the opposite direction, and was increased in the presence of quinidine and verapamil. 4. These results suggest that P-glycoprotein is involved in the biliary excretion of T-5557 and the decrease in the transport activity as well as the increase in plasma protein binding caused the elevated plasma concentration and bioavailability of T-5557 in AA rats.

Administration, Oral↗

PubMed2002

Decreased hepatobiliary transport of methotrexate in adjuvant arthritis rats.

1. We investigated the difference in hepatobiliary transport of methotrexate in normal and adjuvant arthritis (AA) rats and substantiated the expression level of multidrug resistance-associated protein 2 (MRP2) in the liver. 2. Biliary clearance of methotrexate in normal and AA rats was calculated from plasma concentrations and biliary excretion following intravenous infusion and hepatic uptake clearance was estimated from an integration plot using methotrexate concentrations in plasma and liver. 3. Biliary clearance of methotrexate in AA rats was 2.30 +/- 0.23 ml min(-1) kg(-1) (mean SD) and significantly lower than in normal rats (8.42 +/- 0.81 ml min(-1) kg(-1)). The uptake clearance of methotrexate in AA rats was also lower than in normal rats (0.138 versus 0.278 ml min(-1) g liver(-1)). 4. MRP2 in the liver was detected by fluorescein isothiocyanate-labelled antibody and visualized using a confocal laser microscope system. The expression level of MRP2 in AA rats was very low compared with normal rats, indicating a down-regulation in AA rats. 5. In conclusion, biliary clearance of methotrexate was decreased due to the lower activities in both uptake and canalicular secretion, suggesting that several active transporters in the liver, including MRP2, are down-regulated in AA rats.

Animals↗

PubMed1998

Dexamethasone prevents the decrease of bone mineral density in type II collagen-induced rat arthritis model.

This study demonstrated the decrease of bone mineral density (BMD) in the type II collagen (CII)-induced arthritis (CIA) model in rats and the relationship between BMD and paw edema and the effect of dexamethasone-21-phosphate (DEX). The paw swelling occurred on Day 10 and reached its peak on Day 18 after CII injection. BMD in the CII-injected group is lower than that in the control group. BMD in the proximal and distal regions of the femur largely decreased in comparison with that of the middle region. The oral administration of DEX (0.1 mg/kg) inhibited the swelling and decrease of BMD in all three regions of the femur.

Animals↗

PubMed1997

The effect of dexamethasone on the expression of activated NF-kappa B in adjuvant arthritis.

The transcription factor NF-kappa B plays a significant role in inflammatory diseases. In this study we have investigated the expression of activated NF-kappa B p65 subunit in the rat adjuvant arthritis model in a 28-day time-course experiment using immunohistochemistry. The expression of p65 was detected in the synovial lining layer and around the blood vessels in the inflamed synovium as early as Day 3 post-adjuvant injection. The cells that expressed p65 in the synovial lining were thought to be macrophage-like synoviocytes. The expression was stronger in the injected hindpaw than that in the noninjected hindpaw. Dexamethasone treatment at 1 mg/kg p.o. (Days 0-20) suppressed both the hindpaw edema and increase in p65 expression. Withdrawal of the treatment caused increases in both p65 expression and paw volume. Together these suggest that activated NF-kappa B was specifically expressed in the arthritic synovium and may play a significant role in the development of arthritis.

Animals↗

PubMed1997

Changes in bone mineral density in rat adjuvant arthritis.

This study demonstrates that systemic and local decreases in bone mineral density (BMD) occurred with Freund's complete adjuvant injection in the rat right footpad using dual energy X-ray absorptiometry. The rats were assigned to either adjuvant-treated or non-treated control groups composed of eight animals each. There was significant decrease in BMD in the adjuvant group compared to the control group at the distal region of femur or proximal region of tibia on Day 7 post-adjuvant injection (P < 0.05). On the other hand, the femur or tibia of the noninjected side showed a smaller and delayed decrease in BMD than did the injected side. These decreases in BMD were seen in not only the trabecular but also the cortical bone. In addition, the vertebrae also showed delayed but significant decrease (P < 0.05) in BMD on Day 21.

Animals↗

PubMed1997

Selective cleavages of tRNAPhe with secondary and tertiary structures by enediyne antitumor antibiotics.

Some enediyne antitumor antibiotics induce site-selective cleavages for yeast tRNA(Phe) with three-dimensional structure. Of special interest is the fact that tRNA(Phe) is specifically cleaved at the anticodon arm regions by C-1027 and esperamicin A1 in the presence of Mg2+ ions. Although neocarzinostatin strongly breaks tRNA(Phe) at 5'-GPu steps in the absence of magnesium ions, its cleavage ability is completely lost in the presence of 100 microM Mg2+ ions. Dynemicin A, which favors an intercalative binding, causes no strand scissions for the RNA with secondary and tertiary structures. This cutting of tRNA(Phe) may reveal that RNA as well as DNA constitutes a therapeutically relevant target for certain enediyne antitumor antibiotics.

Antibiotics, Antineoplastic↗

PubMed1995

RNA cleavage by C-1027 chromophore, an enediyne antitumor antibiotic: high selectivity to an anticodon arm.

This study demonstrates unique reactivity of the C-1027 chromophore toward a tRNA(phe). In the presence of Mg2+ ions where the tRNA(phe) attains a stable three-dimensional structure, the enediyne chromophore exhibits high cleavage selectivity to the anticodon arm. The present reactivity of the C-1027 chromophore is useful in development of new chemical probes for mapping of tertiary RNA structure. Considering the paucity of RNA repair mechanisms, RNA may be also an important biological target for certain enediyne antibiotics.

Aminoglycosides↗

PubMed1993

Cleavage of yeast tRNA(phe) with Ni(III) and Co(III) complexes of bleomycin.

The BLM-Ni(III) complex preferentially cleaves guanine residues at D loop and anticodon loop of yeast tRNA(phe) by aniline treatment, whereas the BLM-Co(III) complex degrades certain 5'-AN sites of the minor groove region after irradiation of UV light. These cleavage features are clearly different from that of the BLM-Fe(II) complex.

Base Sequence↗