Preclinical/Animal Transporters

Bcrp - cynomolgus monkey

ABCG2, more commonly referred to as BCRP (Breast Cancer Resistance Protein), is an efflux transporter that serves two major drug transport functions. Firstly, it restricts the distribution of its substrates into organs such as the brain, testes, placenta, and across the gastrointestinal tract (GIT). Secondly, it eliminates its substrates from excretory organs, mediating both biliary and renal excretion, and occasionally direct gut secretion. Although less well studied than e.g. MDR1, BCRP is generally co-expressed with MDR1, and shares many of its substrates, inhibitors and inducers. Of its known substrates, rosuvastatin has been implicated in DDI, especially with perpetrator drugs that also inhibit OATPs (e.g. cyclosporine). It is probable that a synergy exists between the action of BCRP, MDR1, and the drug-metabolizing enzyme CYP3A4, particularly in the GIT.
BCRP is included in the list of important drug transporters that both the FDA and EMA consider necessary to investigate regarding liabilities for NCEs. Drugs whose ADME, and bioavailability in particular, is influenced by BCRP may require clinical investigation to reveal a potential DDI with potent clinical BCRP inhibitors. For instance, since the GIT absorption of rosuvastatin is modulated by BCRP, it may be necessary to study the impact of BCRP inhibitors on the oral absorption of rosuvastatin. Because of the potential synergy between BCRP, CYP3A4, and MDR1, a clinical investigation examining the contribution of both drug transporters and enzymes to drug ADME may be necessary.
Cynomolgus monkeys (Macaca fascicularis) are widely used as non-human primate species in preclinical studies and in developmental toxicity studies for biopharmaceuticals, due to their evolutionary closeness and physiological similarity to humans. Oral bioavailability in monkeys appears to be significantly lower than in human however, and the discrepancy primarily stems from lower intestinal availability [1]. Compounds that are excreted largely unchanged and are not efflux transporter substrates show good cross species correlation. However, compounds that undergo CYP3A metabolism and/or are efflux transporter substrates show poor correlation. This observation is supported by tissue mRNA data that demonstrate significantly higher expression of efflux transporters and CYP3A metabolic enzymes at the brush border membrane of monkey small intestine compared to human or rodent [2-5]. Quantitative knowledge of species differences of transporters, especially at the protein and functional level is still limited. Ito et al. determined expression levels of membrane proteins in cynomolgus monkey brain microvessels, which constitute the BBB, quantitatively by LC-MS/MS [7]. Comparison with their previously reported results for mouse brain microvessels [6] indicates that there is a pronounced species difference between monkey and mouse. Bcrp expression in the monkey was more than 3-fold higher than that in mouse, whereas Mdr1 and Mrp4 expression levels were lower than those in mouse [7]. However, Bcrp expression was more than 3-fold higher than Mdr1 in cynomolgus monkey BBB with an overall Bcrp expression that was 1.75-fold higher in monkeys compared with humans. Furthermore, BCRP protein levels were 1.34-fold higher than those of MDR1 in isolated human brain microvessels; whereas mice exhibited 3-fold higher Mdr1 protein levels than Bcrp protein levels in brain capillaries [6]. These results suggest that the functional role of BCRP relative to MDR1 could be greater in the human than in the mouse BBB. Therefore, prediction of human brain penetration based on mouse studies could potentially overestimate the impact of MDR1 and underestimate the impact of BCRP. Such observations suggest that cynomolgus monkeys are likely to be more accurate in predicting human brain penetration compared with mouse models, with a risk of overestimating BCRP impact [8, 7].


1.     Chiou, W. L.; Buehler, P. W. Comparison of oral absorption and bioavailability of drugs 2 between monkey and human. Pharm. Res. 2002, 19, 868-74.
2.    Wang et al, Interspecies Variability in Expression of Hepatobiliary Transporters across Human, Dog, Monkey, and Rat as Determined by Quantitative Proteomics Drug Metab Dispos 43:367–374, March 2015
3.    Prueksaritanont, T.; Gorham, L. M.; Hochman, J. H.; Tran, L. O.; Vyas, K. P.  Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. Drug Metab. Dispos. 1996, 24, 634-42.
4.    Kaji, H.; Kume, T. Glucuronidation of 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetic 7 acid (TA-1801A) in humans: species differences in liver and intestinal microsomes. Drug Metab. Pharmacokinet. 2005, 20, 206-11.
5.    Chu, X.; Bleasby, K.; Evers, R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin. Drug 11 Metab. Toxicol. 2013, 9, 237-52.
6.    Kamiie J, Ohtsuki S, Iwase R, Ohmine K, Katsukura Y, Yanai K, Sekine Y, Uchida Y, Ito S, Terasaki T. 2008. Quantitative atlas of membrane transporter proteins: Development and application of a highly sensitive simultaneous LC/MS/MS method combined with novel in-silico peptide selection criteria. Pharm Res 25:1469–1483
7.    Ito et al., Quantitative Membrane Protein Expression at the Blood–Brain Barrier of Adult and Younger Cynomolgus Monkeys Journal of Pharmaceutical Sciences, Vol. 100, No. 9, September 2011
8.    Uchida Y, Ohtsuki S, Katsukura Y, Ikeda c, Suzuki T, Kamiie J, Terasaki T (2011b) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117(2):333–345.

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