TY - JOUR T1 - Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 807 LP - 810 DO - 10.1124/dmd.107.017624 VL - 36 IS - 5 AU - Yoshiaki Kitamura AU - Hisao Koto AU - Shinobu Matsuura AU - Takeshi Kawabata AU - Hiroshi Tsuchiya AU - Hiroyuki Kusuhara AU - Hajime Tsujimoto AU - Yuichi Sugiyama Y1 - 2008/05/01 UR - http://dmd.aspetjournals.org/content/36/5/807.abstract N2 - 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 Cmax 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 AUC0–8 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. The American Society for Pharmacology and Experimental Therapeutics ER -