Modulation of P-Glycoprotein Expression in Hyperthyroid Rat Tissues

Nishio, Naoki; Katsura, Toshiya; Ashida, Kayoko; Okuda, Masahiro; Inui, Kentaro

doi:10.1124/dmd.105.004770

Cited by 19 publications

(18 citation statements)

References 24 publications

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“…Overexpression of P-gp in liver may also be induced by serum components, the expression of which might have changed epileptic rats (Tang et al, 2001). Moreover, changes in hormonal regulation associated with epilepsy (Hamed et al, 2005;Morris and Vanderkolk, 2005) might also induce P-gp in liver as has been shown in a hyperthyroid rat model (Nishio et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Region-Specific Overexpression of P-glycoprotein at the Blood-Brain Barrier Affects Brain Uptake of Phenytoin in Epileptic Rats

Vliet¹,

Schaik²,

Edelbroek³

et al. 2007

J Pharmacol Exp Ther

105

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Recent studies have suggested that overexpression of the multidrug transporter P-glycoprotein (P-gp) in the hippocampal region leads to decreased levels of antiepileptic drugs and contributes to pharmacoresistance that occurs in a subset of epileptic patients. Whether P-gp expression and function is affected in other brain regions and in organs that are involved in drug metabolism is less studied. Therefore, we investigated P-gp expression in different brain regions and liver of chronic epileptic rats, several months after electrically induced status epilepticus (SE), using Western blot analysis. P-gp function was determined by measuring phenytoin (PHT) levels in these brain regions using high-performance liquid chromatography, in the absence and presence of a P-gp-specific inhibitor, tariquidar (TQD). In addition, the pharmacokinetic profile of PHT was determined. PHT concentration was reduced by 20 to 30% in brain regions that had P-gp overexpression (temporal hippocampus and parahippocampal cortex) and not in brain regions in which P-gp expression was not changed after SE. Inhibition of P-gp by TQD significantly increased the PHT concentration, specifically in regions that showed P-gp overexpression. Despite increased P-gp expression in the liver of epileptic rats, pharmacokinetic analysis showed no significant change of PHT clearance in control versus epileptic rats. These findings show that overexpression of P-gp at the blood-brain barrier of specific limbic brain regions causes a decrease of local PHT levels in the rat brain.

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Section: Discussionmentioning

confidence: 99%

Region-Specific Overexpression of P-glycoprotein at the Blood-Brain Barrier Affects Brain Uptake of Phenytoin in Epileptic Rats

Vliet¹,

Schaik²,

Edelbroek³

et al. 2007

J Pharmacol Exp Ther

105

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“…Crude plasma membrane fractions from the small intestine and liver were isolated according to the method of Nishio et al (2005). The protein (12.5 g) isolated from the intestine and liver was separated by 7.5% SDS-polyacylamide gel electrophoresis (PAGE).…”

Section: Methodsmentioning

confidence: 99%

Decreased Oral Absorption of Cyclosporine A after Liver Ischemia-Reperfusion Injury in Rats: The Contribution of CYP3A and P-Glycoprotein to the First-Pass Metabolism in Intestinal Epithelial Cells

Ikemura

Urano²,

Matsuda³

et al. 2008

J Pharmacol Exp Ther

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The bioavailability of orally administrated cyclosporine A (CsA) is poor and variable in liver transplantation recipients. Little information is available about the effect of liver ischemia-reperfusion (I/R) injury, which is associated with liver transplantation, on the intestinal first-pass metabolism of CsA. In the present study, we investigated the pharmacokinetics of CsA after liver I/R and assessed the effect of liver I/R via CYP3A and P-glycoprotein (P-gp) on its intestinal first-pass metabolism. When CsA alone was administrated orally, the area under the concentration-time curve (AUC) in the I/R rats was significantly decreased compared with that in the sham rats. On the other hand, there were no significant differences in the AUC between I/R and sham rats when CsA was administrated intravenously or orally with ketoconazole. After intraloop administration of CsA to the small intestine (upper, middle, and lower portions) of the I/R and sham rats, the AUC 0 -15 min in the upper intestine was significantly lower in the I/R rats than in the sham rats. CYP3A activity and the expression levels of P-gp in the upper intestine of the I/R rats were significantly higher than those of the sham rats. Our study clearly demonstrates for the first time that liver I/R decreases the oral bioavailability of CsA and that this is attributable principally to increased first-pass metabolism mediated by CYP3A and P-gp in the upper small intestine. The present findings provide useful information for the etiology of liver I/R injury and appropriate use of CsA after liver transplantation.

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“…P-GP is expressed in various tissues, including brain, lung, liver, kidney, gastrointestinal tract, skin and muscle tissue [4,5] , and it is considered an important component of the blood-brain barrier (BBB), blood-placenta barrier, blood-testis barrier and other biological barriers in vivo [6,7] . Moreover, P-GP may efflux many substrates, including anticancer agents, calcium channel blockers, antibiotics, cardiac glycosides and immunosuppressants [5,8] . Therefore, concomitant administration of drugs usually has been shown to cause drug-drug interactions via the inhibition of P-GP mediated transport [9] .…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

et al. 2011

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Aim: To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats. Methods: Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123. Results: In 5-and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues. Conclusion: Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent.

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Modulation of P-Glycoprotein Expression in Hyperthyroid Rat Tissues

Cited by 19 publications

References 24 publications

Region-Specific Overexpression of P-glycoprotein at the Blood-Brain Barrier Affects Brain Uptake of Phenytoin in Epileptic Rats

Region-Specific Overexpression of P-glycoprotein at the Blood-Brain Barrier Affects Brain Uptake of Phenytoin in Epileptic Rats

Decreased Oral Absorption of Cyclosporine A after Liver Ischemia-Reperfusion Injury in Rats: The Contribution of CYP3A and P-Glycoprotein to the First-Pass Metabolism in Intestinal Epithelial Cells

Tissue-specific alterations in expression and function of P-glycoprotein in streptozotocin-induced diabetic rats

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