Received for publication July 12, 2007.
Revised January 10, 2008.
Accepted for publication February 14, 2008.

Modest effect of impaired function of P-glycoprotein on the plasma concentrations of fexofenadine, quinidine, and loperamide following oral administration in Collie dogs

Abstract

P-glycoprotein (P-gp), encoded by the multidrug resistance 1 gene (MDR1/ABCB1), exhibits very broad substrate specificity, and plays important roles in drug disposition. The purpose of the present study was to examine the effect of impaired P-gp activity on the plasma pharmacokinetics of P-gp substrates in Collie dogs with or without homozygous mutant alleles producing truncated P-gp. Three therapeutic agents, fexofenadine (0.1 mg/kg), quinidine (0.1 mg/kg), and loperamide (0.01 mg/kg), were simultaneously given orally, and their plasma concentration-time profiles were determined. The plasma concentrations of these drugs tended to be higher in dogs with the homozygous mutated allele. The C_max was 53.9 ± 13.1 and 90.7 ± 23.1 ng/mL for fexofenadine, 16.5 ± 3.4 and 20.0 ± 7.9 ng/mL for quinidine, and 80.8 ± 9.0 and 101 ± 15 pg/mL for loperamide, and the AUC_0-8 was 263 ± 62 and 435 ± 95 ngh/mL for fexofenadine, 54.5 ± 11.5 and 75.7 ± 21.8 ngh/mL for quinidine, and 467 ± 85 and 556 ± 91 pgh/mL for loperamide, in homozygous wild type and homozygous mutated dogs, respectively. Only the plasma concentration differences of fexofenadine at 4 to 8 h following oral administration were statistically significant. This result suggests that P-gp limits the oral availability of fexofenadine, but had limited impact for quinidine and loperamide in dogs. Collie dogs with the Mdr1 mutation will be useful for examining the effect of P-gp on the oral availability of drugs.

Key words: ABC transporters, absorption, p-glycoprotein