Effect of excipients on breast cancer resistance protein substrate uptake activity.

Breast cancer resistance protein (BCRP/ABCG2) plays an important role in drug disposition. To examine whether some currently used excipients could inhibit its function, we measured the uptake of [(3)H]mitoxantrone in BCRP-, P-glycoprotein (P-gp)- or green fluorescent protein (GFP)-expressing cells, in the presence or absence of 15 kinds of currently used excipients. Of 15 excipients, five (Cremophor EL, Tween 20, Span 20, Pluronic P85 and Brij 30) increased the uptake of [(3)H]mitoxantrone in BCRP-expressing cells. On the other hand, ten (Cremophor EL, Cremophor RH40, Tween 20, Tween 80, Span 20, Pluronic P85, vitamin E TPGS, Brij 30, Myrj 52 and Gelucire 44/14) significantly increased uptake in P-gp-expressing cells. No significant effects on intracellular ATP levels were observed following treatments with the excipients that inhibited BCRP function. Taken together, this study demonstrated that some excipients might be potent BCRP inhibitors, and there may be differences in the effects of excipients on the functions of BCRP and P-gp.

[1]  Yuichi Sugiyama,et al.  Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2) , 2005, Pharmaceutical Research.

[2]  R. Borchardt,et al.  The Use of Surfactants to Enhance the Permeability of Peptides Through Caco-2 Cells by Inhibition of an Apically Polarized Efflux System , 1996, Pharmaceutical Research.

[3]  H. Melhus,et al.  Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. , 2001, The Journal of pharmacology and experimental therapeutics.

[4]  J. Polli,et al.  Rational use of in vitro P-glycoprotein assays in drug discovery. , 2001, The Journal of pharmacology and experimental therapeutics.

[5]  Y. Lo,et al.  Relationships between the hydrophilic-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Lawrence X. Yu,et al.  Vitamin E-TPGS Increases Absorption Flux of an HIV Protease Inhibitor by Enhancing Its Solubility and Permeability1 , 1999, Pharmaceutical Research.

[7]  Yuichi Sugiyama,et al.  Improvement of the Oral Drug Absorption of Topotecan through the Inhibition of Intestinal Xenobiotic Efflux Transporter, Breast Cancer Resistance Protein, by Excipients , 2007, Drug Metabolism and Disposition.

[8]  A. Kabanov,et al.  Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion , 2001, British Journal of Cancer.

[9]  J. Schellens,et al.  Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. , 2000, Journal of the National Cancer Institute.

[10]  K. Maeda,et al.  Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin , 2005, Molecular Pharmacology.

[11]  Kazuya Maeda,et al.  CONTRIBUTION OF OATP (ORGANIC ANION-TRANSPORTING POLYPEPTIDE) FAMILY TRANSPORTERS TO THE HEPATIC UPTAKE OF FEXOFENADINE IN HUMANS , 2005, Drug Metabolism and Disposition.

[12]  Alfred H. Schinkel,et al.  Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine , 2005, Journal of Pharmacology and Experimental Therapeutics.

[13]  Yuichi Sugiyama,et al.  ABCG2 Transports Sulfated Conjugates of Steroids and Xenobiotics* , 2003, Journal of Biological Chemistry.

[14]  A. V. van Herwaarden,et al.  The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. , 2006, Trends in pharmacological sciences.

[15]  Y. Sugiyama,et al.  Functional Analysis of SNPs Variants of BCRP/ABCG2 , 2004, Pharmaceutical Research.

[16]  E. Hudson,et al.  The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). , 2000, Journal of cell science.