Modest effect of impaired P-glycoprotein on the plasma concentrations of fexofenadine, quinidine, and loperamide following oral administration in collies.
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 x h/ml for fexofenadine, 54.5 +/- 11.5 and 75.7 +/- 21.8 ng x h/ml for quinidine, and 467 +/- 85 and 556 +/- 91 pg x 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.
Kitamura
Yoshiaki
Y
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Koto
Hisao
H
Matsuura
Shinobu
S
Kawabata
Takeshi
T
Tsuchiya
Hiroshi
H
Kusuhara
Hiroyuki
H
Tsujimoto
Hajime
H
Sugiyama
Yuichi
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D005260:Female; D007408:Intestinal Absorption; D008139:Loperamide / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D009154:Mutation; D011802:Quinidine / Q000097:blood* / Q000493:pharmacokinetics; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008139:Loperamide; D016593:Terfenadine; C093230:fexofenadine; D011802:Quinidine