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 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.
Footnotes
-
This work was supported by a Grant-in-Aid for Scientific Research (A) (KAKENHI 17209005) (for Y.S.) and by a Grant-in-Aid for Scientific Research (B) (KAKENHI 18390046) (for H.K.) from Japan Society for the Promotion of Science.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.107.017624.
-
ABBREVIATIONS: ABC, ATP-binding cassette; MDR/Mdr, multidrug resistance; P-gp, P-glycoprotein; AUC, area under the concentration-time curve; AUMC, area under the first-moment curve; MRT, mean residence time.
- Received July 11, 2007.
- Accepted February 14, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|