Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Abstract

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 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 ng⅐h/ml for fexofenadine, 54.5 ؎ 11.5 and 75.7 ؎ 21.8 ng⅐h/ml for quinidine, and 467 ؎ 85 and 556 ؎ 91 pg⅐h/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.

Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers

“…The concentrations of racemic fexofenadine, ( R )‐fexofenadine and ( S )‐fexofenadine were 118.7, 72.0 and 48.3 ng/ml in ABCB1‐1Δ Collies at 1 h, whereas their concentrations were 25.0, 16.5 and 7.7 ng/ml in wild‐type Collies, respectively. These results indicate that the P‐gp deficiency induced by the mutant ABCB1‐1Δ gene enhances the concentration of racemic fexofenadine in the Collie plasma, consistent with the previous studies . Despite higher average concentrations of racemic fexofenadine, ( R )‐fexofenadine and ( S )‐fexofenadine in ABCB1‐1Δ Collies over wild‐type Collies at 0.5 h, there were no significant differences between them ( P > 0.05) (Figure a–c).…”

“…The pharmacokinetics of ( R )‐fexofenadine and ( S )‐fexofenadine in human plasma was determined using HPLC‐UV . Another study using LC‐MS assay indicates that fexofenadine concentration was increased in P‐gp mutant Collies . In our study, two HPLC–fluorescence methods were used to measure the concentration of racemic fexofenadine and its enantiomers in dog plasma.…”

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

“…Loperamide exposure (expressed as AUC 0-last values) and the corresponding variability in that exposure in the Mut dog typically exceeded that of their WT counterparts. With the small number of subjects included in the investigation by Mealey et al (2010), and differences with the results seen by Kitamura et al (2008), the apparent interstudy disparities may simply be a function of "chance." Moreover, we observed that those Collies trending toward a lower adverse response to loperamide (4D) also tended to exhibit lower plasma level variability compared with Mut or 3D Collies.…”

“…However, conflicting reports have been published on the impact of this ABCB1-1Δ polymorphism on canine plasma loperamide concentrations. For example, Kitamura et al (2008) observed that a pharmacological dose of loperamide (0.01 mg/kg) was associated with elevated plasma loperamide levels in Collies homozygous for the ABCB1-1Δ mutation. Conversely, no corresponding differences in loperamide PK were reported at a suprapharmacological dose of 0.2 mg/kg (Mealey et al, 2010).…”

Rapid genotyping assays for the 4–base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs

“…7,20,22 There is also a report that the pharmacokinetic parameters of fexofenadine and quinidine are significantly altered in MDR1 mutant dogs. 18 Regarding some of these drugs, brain penetration is highly increased, and the dogs develop severe neurotoxicosis, even when the drugs are administered at a normal therapeutic dosage, as in the case of ivermectin and doramectin. 7,20,22 Several different genotyping methods have been described for the detection of the 4-bp deletion mutation.…”