During the drug discovery development, most new chemical entities (NCEs) suffer from limiting oral absorption after an oral administration. Besides the first-pass metabolism, some other factors such as aqueous solubility, membrane permeability, and active drug efflux can attenuate oral absorption.

About active drug efflux, members of the ATP-binding cassette (ABC) superfamily of efflux transporters can modulate the systemic exposure of NCEs. The major barriers within the body (e.g., small intestine, blood–brain barrier, placenta, kidney, and liver) always express active efflux transporters. Multidrug resistance protein (human MDR1/rodent Mdr1, ABCB1) is the prototypical ABC transporter first identified through studies on multidrug resistance.

In this article, we will introduce an orally active dual MDR1/BCRP inhibitor, CP-100356.

The IC50 for inhibiting MDR1-mediated Calcein-AM transport and BCRP-mediated Prazosin are 0.5 and 1.5 µM, respectively. In human MDR1-transfected MDCKII cells, CP-100356 inhibits acetoxymethyl Calcein (Calcein-AM) uptake with an IC50 of 0.50 µM. And it inhibits Digoxin transport with an IC50 of 1.2 µM.

This compound is also a weak inhibitor of OATP1B1 (IC50=66 µM). CP-100356 inhibits OATP1B1-mediated uptake of Estradiol 17β-D-Glucuronide, with an IC50 of ~66 µM. However, CP-100356 is devoid of MRP2 and major human P450 enzyme inhibition (IC50>15 µM) in the competitive inhibition study.

In vivo, CP-100356 increases the systemic exposure of Fexofenadine (36- and 80-fold increase in Cmax and AUC at the dose of 24 mg/kg) in rats. The Cmax, Tmax, and AUC for CP-100356 are 360 ng/ml, 0.83 ng/ml and 1100 ng h/mL, respectively. Additionally, the T1/2 (h) and F% for CP-100356 are 0.98 h and 60%, respectively.

Female CD-1 and CF-1 mice receive a gavage dose of 0.4 mg/kg BW ivermectin. In CD-1 mice, ivermectin B1a could not be detected in plasma, while brain levels are 1.38-1.98 ng/g. Pretreatment with CP-100,356 results in plasma levels of 17.2-18.7 ng/ml and brain levels of 1.95-2.13 ng/g.

In conclusion, as an MDR inhibitor, CP-100,356 is a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in vivo.


[1]. Kalgutkar AS, et, al. J Pharm Sci. 2009 Dec;98(12):4914-27.