In Vivo Assessment of the Impact of Efflux Transporter on Oral Drug Absorption Using Portal Vein–Cannulated Rats

Abstract

The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal veincannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

Pharmacokinetics of mangiferin and its metabolite—norathyriol, Part 2: Influence of UGT, CYP450, P‐gp, and enterobacteria and the potential interaction in Rhizoma Anemarrhenae decoction with timosaponin B2 as the major contributor

“…100.65 ± 33.07 ng/mL, P < 0.05) and 48% (1,457.59 ± 487.86 h·ng/mL vs . 982.29 ± 357.09 h·ng/mL, P > 0.05) increase in rats with the pretreatment of zosuquidar, a specific P‐gp transporter with the oral dosage of 30 mg/kg . Additionally, the prolonged T max (2.17 ± 0.98 h vs .…”

“…Consistent to the in vitro experiment (as seen in Part 1) that the generation of NTR could happen in the MGF‐incubating enterobacteria samples, but not in hepatocytes, and it only accounted for 0.1% of the adding MGF concentration after incubation within 72 h, as well as where the MGF concentration remained very limited changes, implying that NTR production mainly mediated by intestinal bacteria, but it accounted for a tiny percentage of the parent drug in the intestinal lumen and thereby it was not sufficiently enough to change the PK profiles of MGF in vivo . Compared with MGF treatment alone, the C max and AUC of MGF displayed 210% and 48% enhancement in rats with the pretreatment of zosuquidar, a specific P‐gp inhibitor that significantly increased the exposure of fexofenadine in rats by the inhibition of P‐gp transporters at the oral dosage of 30 mg/kg . Correspondingly, verapamil, a typical P‐gp inhibitor, could enhance the transport on MGF transport in Caco‐2 cell monolayer model .…”

“…Compared with MGF treatment alone, the C max and AUC of MGF displayed 210% and 48% enhancement in rats with the pretreatment of zosuquidar, a specific P-gp inhibitor that significantly increased the exposure of fexofenadine in rats by the inhibition of P-gp transporters at the oral dosage of 30 mg/kg [20]. Correspondingly, verapamil, a typical P-gp inhibitor, could enhance the transport on MGF transport in Caco-2 cell monolayer model [6].…”

Application of a Human Intestinal Epithelial Cell Monolayer to the Prediction of Oral Drug Absorption in Humans as a Superior Alternative to the Caco-2 Cell Monolayer

“…9 Matsson et al (2005) reported that the rank-order correlation between the Fa of P-gp substrates and their P app values determined in the Caco-2 cell monolayer was better than that in the 2/4/A1 cell monolayer. Furthermore, the Fa value of sulfasalazine, the intestinal absorption of which was limited by BCRP and MRP2 in Caco-2 cells, 30 in rats, 31,32 and in clinical studies, [33][34][35] was overpredicted in 2/4/A1 cells by the best-fitted regression line for the relationship between the P app value in 2/4/A1 cells and observed Fa value. 6 However, the Fa value for the same drug was predicted well by P app values in HIECs (observed Fa ¼ 13% vs. predicted Fa ¼ 15% obtained from the best-fitted sigmoidal relationship in Fig.…”

The Impact of Breast Cancer Resistance Protein (BCRP/ABCG2) on Drug Transport Across Caco-2 Cell Monolayers

“…These results demonstrate that BCRP significantly contributes to the transport of these drugs in Caco-2 cell monolayers. Matsuda et al (2013) demonstrated that the intestinal availability of topotecan and sulfasalazine after oral administration in rats was increased by approximately 4-fold following the preadministration of Ko143. Moreover, Dahan et al (2009) showed that the BCRP inhibitors fumitremorgin C and pantoprazole significantly increased the AP-to-BL transport of sulfasalazine.…”