RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 807
OP 810
DO 10.1124/dmd.107.017624
VO 36
IS 5
A1 Yoshiaki Kitamura
A1 Hisao Koto
A1 Shinobu Matsuura
A1 Takeshi Kawabata
A1 Hiroshi Tsuchiya
A1 Hiroyuki Kusuhara
A1 Hajime Tsujimoto
A1 Yuichi Sugiyama
YR 2008
UL http://dmd.aspetjournals.org/content/36/5/807.abstract
AB 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