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Interaction of triazolam and ketoconazole in P-glycoprotein-deficient mice

Lisa L von Moltke1, Brian W Granda, Jeffrey M Grassi

  • 1Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. lisa.vonmoltke@tufts.edu

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|July 20, 2004
PubMed

Insights

P-glycoprotein (P-gp) does not significantly affect triazolam (TRZ) brain distribution. Ketoconazole (KET) brain levels are higher in P-gp deficient mice, suggesting KET may be a substrate for blood-brain barrier efflux.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Drug Metabolism

Background:

  • P-glycoprotein (P-gp) is a key efflux transporter at the blood-brain barrier (BBB).
  • Understanding P-gp's role in drug distribution is crucial for predicting drug efficacy and toxicity.
  • Triazolam (TRZ), a benzodiazepine, and ketoconazole (KET), an antifungal, are substrates for drug-metabolizing enzymes like CYP3A.

Purpose of the Study:

  • To investigate the role of P-gp in the BBB distribution of triazolam (TRZ) and ketoconazole (KET).
  • To examine the interaction between TRZ and KET concerning their distribution and potential P-gp mediated transport.
  • To assess the impact of P-gp deficiency on TRZ and KET brain-to-serum concentration ratios.

Main Methods:

  • Utilized P-gp deficient (mdr1a(-) or mdr1a/b(-/-)) mice and matched control groups.
  • Administered single intraperitoneal injections of TRZ or KET to assess their distribution.
  • Investigated drug transport in Caco-2 cell monolayers to model intestinal absorption and efflux.

Main Results:

  • TRZ brain concentrations exceeded serum levels in control mice, while KET brain/serum ratios were below 1.
  • P-gp deficient mice showed significantly higher KET brain concentrations and brain/serum ratios compared to controls.
  • KET administration increased TRZ concentrations in serum, liver, and brain, likely due to CYP3A inhibition, but did not alter TRZ brain/serum ratios.

Conclusions:

  • Triazolam (TRZ) does not appear to undergo significant P-glycoprotein-mediated efflux transport at the blood-brain barrier in this model.
  • Ketoconazole (KET) brain penetration is influenced by P-gp, suggesting KET may be a substrate for efflux transport at the BBB.
  • Ketoconazole (KET) impairs the clearance of triazolam (TRZ) but does not enhance its tissue uptake, with interactions likely mediated by CYP3A inhibition.

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