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

K L Mealey; D Waiting; D L Raunig; K R Schmidt; F R Nelson

doi:10.1111/j.1365-2885.2010.01170.x

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

Journal article

Peer reviewed

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

K L Mealey, D Waiting, D L Raunig, K R Schmidt and F R Nelson

Journal of veterinary pharmacology and therapeutics, Vol.33(5), pp.453-460

10/2010

DOI: https://doi.org/10.1111/j.1365-2885.2010.01170.x

Handle:

https://hdl.handle.net/2376/110074

PMID: 20840389

Abstract

Anti-Anxiety Agents - administration & dosage

ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism

Substrate Specificity

Biological Availability

Male

Diazepam - pharmacokinetics

Enzyme Inhibitors - administration & dosage

Anti-Anxiety Agents - pharmacokinetics

Loperamide - pharmacokinetics

Enzyme Inhibitors - pharmacokinetics

HIV Protease Inhibitors - pharmacokinetics

Quinidine - pharmacokinetics

Cyclosporine - pharmacokinetics

Female

Dogs - genetics

Antimalarials - pharmacokinetics

Loperamide - administration & dosage

Diazepam - administration & dosage

Antidiarrheals - pharmacokinetics

Dogs - metabolism

Genotype

HIV Protease Inhibitors - administration & dosage

Quinidine - administration & dosage

Cross-Over Studies

Animals

Antimalarials - administration & dosage

ATP-Binding Cassette, Sub-Family B, Member 1 - genetics

Cyclosporine - administration & dosage

Antidiarrheals - administration & dosage

Nelfinavir - pharmacokinetics

Nelfinavir - administration & dosage

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.

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Title: Oral bioavailability of P-glycoprotein substrate drugs do not differ between ABCB1-1Δ and ABCB1 wild type dogs
Creators: K L Mealey - Veterinary Clinical Pharmacology Laboratory, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA. kmealey@vetmed.wsu.edu
D Waiting
D L Raunig
K R Schmidt
F R Nelson
Publication Details: Journal of veterinary pharmacology and therapeutics, Vol.33(5), pp.453-460
Academic Unit: Veterinary Clinical Sciences, Department of
Publisher: England
Identifiers: 99900547019201842
Language: English
Resource Type: Journal article

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

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