Improvement of the Oral Drug Absorption of Topotecan through the Inhibition of Intestinal Xenobiotic Efflux Transporter, Breast Cancer Resistance Protein, by Excipients

Abstract

ABSTRACT:Recently, breast cancer resistance protein (BCRP/ABCG2) has been shown to limit the oral absorption of its substrates in the intestine. The purpose of this study was to examine whether excipients can be used as inhibitors of BCRP, to improve the oral drug absorption of BCRP substrates. In wild-type mice, Pluronic P85 and Tween 20, given orally 15 min before topotecan administration, increased the area under the plasma concentration-time curve (AUC) of topotecan after oral administration (2.0-and 1.8-fold, respectively). In contrast, Pluronic P85 and Tween 20 were less effective (no significant difference) on the AUC of topotecan after oral administration in Bcrp (؊/؊) mice (1.2-and 1.2-fold, respectively). Pluronic P85 and Tween 20 given orally did not affect significantly the AUC of topotecan after intravenous administration in wild-type and Bcrp (؊/؊) mice. Moreover, we determined the mucosal-to-serosal absorptive transport of topotecan using everted mouse ileum. Pluronic P85 and Tween 20 significantly increased the intestinal absorption rate of topotecan in everted sacs from wild-type mice whereas, in everted sacs from Bcrp (؊/؊) mice, the absorption rate was 2.1-fold greater than that in wild-type mice, and these excipients were not significantly effective. There was no significant difference in the intestinal P-glycoprotein (P-gp) expression and serosal-to-mucosal secretory transport of rhodamine 123, a typical P-gp substrate. Taken together, these results suggest that Pluronic P85 and Tween 20 can improve the oral bioavailability of BCRP substrates by inhibiting BCRP function in the small intestine.It is well known that active efflux in the intestinal epithelium by ATP-dependent multidrug efflux transporters, such as P-glycoprotein (P-gp), is one of the mechanisms limiting oral absorption of drugs, and thus, inhibition of active efflux is one of the strategies used to improve oral absorption of drugs that are pumped out from the intestinal epithelium into the lumen by efflux transporter systems (van Asperen et al., 1997;Meerum Terwogt et al., 1999). During the past two decades, several inhibitors of efflux transporters have been developed to enhance the bioavailability of their substrates (Hyafil et al., 1993;Dantzig et al., 1996;Wacher et al., 2001;Stewart et al., 2004). Although effective in animal experiments, their clinical applicability has been limited (Breedveld et al., 2006) and, consequently, more effective and safer inhibitors are needed.Excipients, such as surfactants, are extensively used in "passive" pharmaceutical formulations to improve dissolution of poorly soluble drugs. Previously, it has been found that several excipients can inhibit P-gp. Nerurkar et al. (1996) reported that Cremophor EL and Tween 80 enhanced the absorptive transport of a model peptide by inhibiting the secretory directed transport of this peptide in Caco-2 cells. Yu et al. (1999) also reported that vitamin E-TPGS (D-␣-tocopheryl polyethylene glycol succinate) inhibited the efflux system and enhanced the permea...

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…There is an additional approach to bypass intestinal efflux by incorporating into oral drug formulations excipients that inhibit Bcrp function. For example, the excipients Pluronic P85 and Tween 20 improve intestinal absorption of the Bcrp substrate topotecan in wildtype but not Bcrp-null mice (Yamagata et al, 2007).…”

The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?

“…ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ (Zaher et al, 2006) c.34GG and c.421AA/CC/CA: ,2-to 4-fold AUC increases; inconsistent findings between studies (Adkison et al, 2010;Schnepf and Zolk, 2013) No significant association with PK (+dual MDR1/ BCRP inhibitor: pantoprazole) (Adkison et al, 2010); 3.2 max fold AUC increase (+BCRP and enzymes inhibitor: curcumin) (Kusuhara et al, 2012) OATP2B1 substrate (Kusuhara et al, 2012 (Kitamura et al, 2008) c.421CA/AA: 2-to 2.4-fold AUC increases (Zhang et al,. 2006 ;Ieiri et al, 2009;Keskitalo et al, 2009b) 1.6 max fold AUC increase (+ dual OATP/BCRP inhibitors: eltrombopag, ritonavir) (Allred et al, 2011); 7-fold increase (+multiple transporters and enzymes inhibitor: CsA) (Schnepf and Zolk, 2013) (Mizuno et al, 2012); no impact on plasma exposure but on brain distribution (Tang et al, 2012;Schnepf and Zolk, 2013) c.421CA/AA 1.7-to 3-fold AUC increase (Mizuno et al, 2012) (Yamagata et al, 2007) c.421CA: increase in F from ;30% to ;40%, no significant change in AUC, very small sample size (Sparreboom et al, 2005) Increase in F from ;40% to ;100% (+dual MDR1 / BCRP inhibitor: elacridar) (Schnepf a...…”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…ABCG2 mRNA expression was higher compared to other efflux transporter in the human small intestine, which is a rate-limiting barrier to oral drug absorption [64] . The important impact of ABCG2 on the intestinal absorption was further supported by several knockout mice research, which have indicated that ABCG2 affects the pharmacological and toxicological behavior of many drugs [65][66][67] . Also, polymorphisms might influence the role of ABCG2 in intestinal absorption.…”