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.

Induction of chemoresistance in a cultured canine cell line by retroviral transduction of the canine multidrug resistance 1 gene.

OBJECTIVE: To induce chemoresistance in a normal canine cell line through the transduction of the canine multidrug resistance 1 gene (mdr1). SAMPLE POPULATION: Madin-Darby canine kidney (MDCK) epithelial cell line. PROCEDURES: The full-length canine mdr1 cDNA clone isolated in our laboratory was inserted into a Moloney murine leukemia virus-based vector to construct the retroviral vector, pLNC-cMDR1. After retroviral transduction of pLNC-cMDR1 into MDCK cells, the expression and function of the P-glycoprotein, a product of mdr1, were assessed by immunoblotting, measurement of rhodamine123 (Rh123) retention, and drug sensitivity assays. RESULTS: P-glycoprotein was strongly expressed in cells transduced with pLNC-cMDR1. This P-glycoprotein was fully functional, as demonstrated by the decreased Rh123 retention and the increased resistance to chemotherapeutic drugs. Measured as 50% inhibitory concentrations, resistance increased 59 times to vincristine and 25 times to doxorubicin in MDCK cells after transduction of pLNC-cMDR1. CONCLUSIONS AND CLINICAL RELEVANCE: Transduction of canine mdr1 is an effective method for inducing chemoresistance in normal canine cells. This system may be applicable to the induction of drug resistance in hematopoietic cells.