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Research ArticleArticle

INTERACTION OF TRIAZOLAM AND KETOCONAZOLE IN P-GLYCOPROTEIN-DEFICIENT MICE

Lisa L. von Moltke, Brian W. Granda, Jeffrey M. Grassi, Michael D. Perloff, Daesety Vishnuvardhan and David J. Greenblatt
Drug Metabolism and Disposition August 2004, 32 (8) 800-804; DOI: https://doi.org/10.1124/dmd.32.8.800
Lisa L. von Moltke
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Brian W. Granda
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Jeffrey M. Grassi
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Michael D. Perloff
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Daesety Vishnuvardhan
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David J. Greenblatt
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Abstract

The role of P-glycoprotein (P-gp) on the distribution of the benzodiazepine triazolam (TRZ) and the azole antifungal agent ketoconazole (KET), and on the TRZ-KET interaction, was studied using mdr1a(-) or mdr1a/b(-/-) mice (P-gp-deficient mice) and matched controls. TRZ and KET also were studied in Caco-2 cells in Transwell culture. After single i.p. injections of TRZ or KET in separate groups of control mice, brain concentrations of TRZ exceeded those in serum [brain/serum area under the concentration curve (AUC) ratio, 5.0], whereas brain/serum AUC ratios for KET were approximately 0.5. On the basis of single time points, brain concentrations of TRZ, or brain/serum ratios, were similar in P-gp-deficient animals compared with controls, whereas P-gp-deficient animals had significantly higher KET brain concentrations and brain/serum ratios. Coadministration of KET with TRZ increased TRZ concentrations in serum, liver, and brain, both in controls and in P-gp-deficient animals, probably attributable to impairment by KET of CYP3A-mediated clearance of TRZ. However, KET did not increase brain/serum ratios of TRZ in either group. In Caco-2 cells, basal-to-apical flux of TRZ was higher than apical-to-basal flux. However, verapamil (100 μM) did not alter flux in either direction. KET inhibited basal-to-apical transport of rho-damine-123, with a 50% inhibitory concentration of 2.7 μM. Thus, TRZ does not appear to undergo measurable blood-brain barrier efflux transport by P-gp in this animal model. KET impairs clearance of TRZ but does not increase tissue uptake. However, KET itself may be a substrate for efflux transport at the blood-brain barrier.

Footnotes

  • This work was supported in part by Grants MH-58435, DA-05258, DA-13209, DK/AI-58496, DA-13834, AG-17880, AT-01381, and RR-00054 from the Department of Health and Human Services.

  • ABBREVIATIONS: P-gp, P-glycoprotein; CNS, central nervous system; TRZ, triazolam; B, basolateral; A, apical; KET, ketoconazole; Rh123, rhodamine 123; HPLC, high-performance liquid chromatography; IC50, 50% inhibitory concentration; AUC, area under the concentration curve.

    • Received January 30, 2004.
    • Accepted April 15, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (8)
Drug Metabolism and Disposition
Vol. 32, Issue 8
1 Aug 2004
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Research ArticleArticle

INTERACTION OF TRIAZOLAM AND KETOCONAZOLE IN P-GLYCOPROTEIN-DEFICIENT MICE

Lisa L. von Moltke, Brian W. Granda, Jeffrey M. Grassi, Michael D. Perloff, Daesety Vishnuvardhan and David J. Greenblatt
Drug Metabolism and Disposition August 1, 2004, 32 (8) 800-804; DOI: https://doi.org/10.1124/dmd.32.8.800

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Research ArticleArticle

INTERACTION OF TRIAZOLAM AND KETOCONAZOLE IN P-GLYCOPROTEIN-DEFICIENT MICE

Lisa L. von Moltke, Brian W. Granda, Jeffrey M. Grassi, Michael D. Perloff, Daesety Vishnuvardhan and David J. Greenblatt
Drug Metabolism and Disposition August 1, 2004, 32 (8) 800-804; DOI: https://doi.org/10.1124/dmd.32.8.800
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