Interindividual Variability in the Hepatic Expression of the Human Breast Cancer Resistance Protein (BCRP/ABCG2): Effect of Age, Sex, and Genotype

Breast cancer resistance protein (BCRP), an efflux transporter expressed at the bile canalicular membrane, is responsible for the biliary clearance of many drugs. Data on the interindividual variability of hepatic BCRP expression are needed for in vitro to in vivo extrapolation of the biliary clearance of a BCRP substrate drug. Therefore, we measured the expression of BCRP in human livers (n = 65) by liquid chromatography coupled with tandem mass spectrometry. A calibration curve was generated using a synthetic signature peptide (SSLLDVLAAR) as the calibrator and the corresponding synthetic stable isotope-labeled peptide as the internal standard. The analytical method was accurate and precise. BCRP expression in 50 livers, where it was measurable, was 137.9 ± 42.1 atmol/μg of membrane protein (range 69.7-246.4 atmol/μg of membrane protein). BCRP expression was not associated with age (7-70 years), sex, or mRNA expression. BCRP expression in livers with the variant C421A (rs2231142) allele (14 heterozygotes, two homozygotes; among these, eight livers were below lower limit of quantification) was significantly lower than that in the wild-type livers (p < 0.002). Integration of these data with data on the hepatic expression of other transporters will allow refinement of physiologically based pharmacokinetic models to predict the pharmacokinetics, hepatic exposure, and drug-drug interactions of drugs (and/or their metabolites). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:787-793, 2013