1. Academic Validation
  2. Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

  • Eur J Drug Metab Pharmacokinet. 2018 Oct;43(5):599-606. doi: 10.1007/s13318-018-0474-x.
Peter Matzneller 1 Manuel Kussmann 2 Sabine Eberl 1 Alexandra Maier-Salamon 3 Walter Jäger 3 Martin Bauer 1 Oliver Langer 4 5 6 Markus Zeitlinger 1 Wolfgang Poeppl 2 7
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
  • 2 Department of Internal Medicine I, Clinical Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, Vienna, Austria.
  • 3 Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
  • 4 Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. [email protected].
  • 5 Biomedical Systems, Center for Health and Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria. [email protected].
  • 6 Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. [email protected].
  • 7 Department of Dermatology and Tropical Medicine, Military Medical Cluster East, Austrian Armed Forces, Vienna, Austria.
Abstract

Background and objective: P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood-brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration.

Methods: Two different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice.

Results: In contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B.

Conclusion: The present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound.

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