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Research ArticleArticle

Pharmacokinetic Interaction of Cytochrome P450 3A-Related Compounds with Rhodamine 123, a P-Glycoprotein Substrate, in Rats Pretreated with Dexamethasone

Ryoko Yumoto, Teruo Murakami, Maki Sanemasa, Reishi Nasu, Junya Nagai and Mikihisa Takano
Drug Metabolism and Disposition February 2001, 29 (2) 145-151;
Ryoko Yumoto
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Teruo Murakami
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Maki Sanemasa
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Reishi Nasu
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Junya Nagai
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Mikihisa Takano
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Abstract

The effect of pretreatment with dexamethasone (DEX) on drug-drug interactions between rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, and midazolam, a cytochrome P450 (CYP) 3A substrate, or verapamil, a P-gp/CYP3A substrate, was studied in rats. Rats were pretreated with DEX (100 mg/kg/day, oral) for 2 days. Western blot analysis with a monoclonal antibody for P-gp, C219, revealed that DEX pretreatment increased P-gp level in the intestine 1.9-fold, but not in the liver. In vitro metabolism study of erythromycin in microsomal suspensions indicated the 9.7-fold increase of CYP3A activity in the liver, but not in the intestine, by DEX pretreatment. In an in vivo study, DEX pretreatment increased P-gp-mediated exsorption clearance of Rho123 from blood to the intestinal lumen approximately 2-fold, but not biliary clearances, in good agreement with the results of Western blot analysis. In untreated rats, midazolam (100 μM) or verapamil (30 or 100 μM) added in the intestinal perfusate (single perfusion) decreased the exsorption clearance and biliary clearance of Rho123 by approximately 30 to 50%. In DEX-pretreated rats, however, the inhibitory potency of midazolam in the liver significantly decreased compared with that in untreated rats, although the potency in the intestine did not change. The inhibitory potency of verapamil decreased both in the intestine and liver by DEX pretreatment. In conclusion, it was demonstrated that DEX pretreatment affects not only P-gp-mediated disposition of Rho123 but also pharmacokinetic interactions of P-gp/CYP3A-related compounds with Rho123, probably because concentrations of substrates/inhibitors at target sites such as the intestine and liver are varied.

Footnotes

  • Send reprint requests to: Mikihisa Takano, Ph.D., Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima University,1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail:takanom{at}pharm.hiroshima-u.ac.jp

  • This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture in Japan and by a grant from The Naito Foundation.

  • Abbreviations used are::
    P-gp
    P-glycoprotein
    CLbile
    biliary excretion clearance
    CLbile*
    biliary excretion clearance normalized with hepatic drug concentration
    CLexp
    intestinal exsorption clearance
    CLtotal
    total plasma clearance
    Cpss
    steady-state plasma concentration
    CsA
    cyclosporin A
    CYP
    cytochrome P450
    DEX
    dexamethasone
    DMSO
    dimethyl sulfoxide
    Rho123
    rhodamine 123
    mdr
    multidrug resistance gene
    MRP
    multidrug resistance-associated protein
    • Received May 23, 2000.
    • Accepted October 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (2)
Drug Metabolism and Disposition
Vol. 29, Issue 2
1 Feb 2001
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Research ArticleArticle

Pharmacokinetic Interaction of Cytochrome P450 3A-Related Compounds with Rhodamine 123, a P-Glycoprotein Substrate, in Rats Pretreated with Dexamethasone

Ryoko Yumoto, Teruo Murakami, Maki Sanemasa, Reishi Nasu, Junya Nagai and Mikihisa Takano
Drug Metabolism and Disposition February 1, 2001, 29 (2) 145-151;

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Research ArticleArticle

Pharmacokinetic Interaction of Cytochrome P450 3A-Related Compounds with Rhodamine 123, a P-Glycoprotein Substrate, in Rats Pretreated with Dexamethasone

Ryoko Yumoto, Teruo Murakami, Maki Sanemasa, Reishi Nasu, Junya Nagai and Mikihisa Takano
Drug Metabolism and Disposition February 1, 2001, 29 (2) 145-151;
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