Assessment of contribution of BCRP to intestinal absorption of various drugs using portal-systemic blood concentration difference model in mice.

Iichiro Kawahara,Takuya Fujita,Akira Yamamoto,Yusuke Kono,Satoyo Nishikawa

doi:10.1002/prp2.544

Abstract

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P‐glycoprotein (P‐gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco‐2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal‐systemic blood concentration (P‐S) difference method in wild‐type (WT), Bcrp(−/−), and Mdr1a/1b(−/−) mice. In addition, we also calculated a rate of BCRP contribution (Rbcrp). Ciprofloxacin and nitrofurantoin showed the low Rbcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(−/−) mice. Moreover, their Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco‐2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process.

Highlights

Oral drug administration has been most frequently used in clinical because it has several advantages against other administration routes, such as easy to use, high safety, good patient compliance, and low cost
We evaluated the contribution of breast cancer resistance protein (BCRP) and P-gp to the intestinal absorption of model drugs, ciprofloxacin, nitrofurantoin, topotecan, and sulfasalazine, by portalsystemic blood concentration (P-S) difference method in WT, breast cancer resistance protein (Bcrp)(−/−), and Mdr1a/1b(−/−) mice
AUCpv and AUCsys of nitrofurantoin after oral administration in Bcrp(−/−) mice (3414 nmol/ L·h and 2557 nmol/L·h) and in Mdr1a/1b(−/−) mice (3182 nmol/L·h and 2345 nmol/L·h) were approximately 1.5-fold higher than those in WT mice (2545 nmol/L·h and 1835 nmol/L·h). These results suggest that both BCRP and p-gp are involved in the intestinal absorption of nitrofurantoin

Summary

| INTRODUCTION

Oral drug administration has been most frequently used in clinical because it has several advantages against other administration routes, such as easy to use, high safety, good patient compliance, and low cost. We evaluated the contribution of BCRP, as well as P-gp, which is a representative drug efflux transporter, to intestinal drug absorption using a recirculatory model for portal-systemic blood concentration (P-S) difference method (Figure 1) in Bcrp(−/−) and Mdr1a/1b(−/−) mice.[10,11] This method was developed to separately evaluate the rate and extent of absorption from the gastrointestinal tract into the portal system and disposition of a drug in the body We here applied this method for various model compounds, and estimated the apparent local absorption ratio from the gastrointestinal tract into the portal system (FaFg) in WT, Bcrp(−/−), and Mdr1a/1b(−/−) mice. We assessed the correlation of in vivo AQ with in vitro AQ obtained from in vitro Caco-2 permeability studies

| MATERIALS AND METHODS

| Analytical methods

Findings

| DISCUSSION