Oral bioavailability of P-glycoprotein substrate drugs do not differ between ABCB1-1Δ and ABCB1 wild type dogs

Authors

  • K. L. MEALEY,

    1. Veterinary Clinical Pharmacology Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
    Search for more papers by this author
  • D. WAITING,

    1. Veterinary Clinical Pharmacology Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
    Search for more papers by this author
  • D. L. RAUNIG,

    1. Department of Global Statistics, Pfizer Global Research and Development, Groton Laboratories, Groton, CT, USA
    Search for more papers by this author
  • K. R. SCHMIDT,

    1. Department of Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT, USA
    Search for more papers by this author
  • F. R. NELSON

    1. Department of Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT, USA
    Search for more papers by this author

Katrina L. Mealey, Veterinary Clinical Pharmacology Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA. E-mail: kmealey@vetmed.wsu.edu

Abstract

Mealey, K.L., Waiting, D., Raunig, D.L., Schmidt, K.R., Nelson, F.R. Oral bioavailability of P-glycoprotein substrate drugs do not differ between ABCB1-1Δ and ABCB1 wild type dogs. J. vet. Pharmacol. Therap. 33, 453–460.

Previous studies have indicated that intestinal P-glycoprotein (P-gp) limits the oral bioavailability of substrate drugs and alters systemic pharmacokinetics. In this study, dogs lacking functional P-gp were used to determine the contribution of P-gp to the oral bioavailability and systemic pharmacokinetics of several P-gp substrate drugs. The P-gp substrates quinidine, loperamide, nelfinavir, cyclosporin and the control (non P-gp substrate) drug diazepam were individually administered intravenously and per os to ABCB1-1Δ dogs, which have a P-gp null phenotype and ABCB1 wildtype dogs. ABCB1-1Δ dogs have been shown to have greater brain penetration of P-gp substrates, but limited information is available regarding oral bioavailability of P-gp substrate drugs in this animal model. Plasma drug concentration vs. time curves were generated and pharmacokinetic parameters were calculated for each drug. There were no differences in oral bioavailability between ABCB1-1Δ dogs and ABCB1 wildtype dogs for any of the drugs studied, suggesting that intestinal P-gp does not significantly affect intestinal absorption of these particular substrate drugs in ABCB1-1Δ dogs. However, small sample sizes and individual variability in CYP enzyme activity may have affected the power of the study to detect the impact of P-gp on oral bioavailability.

Ancillary