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SHORT COMMUNICATION

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (Y.K., H.Ku., Y.S.); Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan (H.Ko., S.M., T.K., Ha.T.); and Pascal Animal Hospital, Saitama, Japan (Hi.T.)

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 collies 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 ng·h/ml for fexofenadine, 54.5 ± 11.5 and 75.7 ± 21.8 ng·h/ml for quinidine, and 467 ± 85 and 556 ± 91 pg·h/ml for loperamide in homozygous wild-type and homozygous mutated dogs, respectively. Only the plasma concentration differences of fexofenadine at 4 to 8 h after oral administration were statistically significant. This result suggests that P-gp limits the intestinal absorption of fexofenadine in dogs. Collies with the Mdr1 mutation will be useful for examining the effect of P-gp on the oral availability of drugs.