In vitro and in vivo data and considerations for potential intestinal BCRP inhibitors
IC50 and Ki values are presented as reported in the respective references, along with the substrate used.
Precipitant | [I2] | Dose | BCRP Parameters | Other Possible Intestinal Interactions | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Ki | IC50 | [I2]/IC50 | In Vivo PK–Based DDI Data | Transporter/Enzyme | IC50 | [I2]/IC50 | In Vivo PK–Based DDI Data | |||
μM | μM | μM | ||||||||
Lapatiniba | 5300b | 1250 mg QD (SS)1 | – | 0.025 CIM2 | 210,000c | Decreased TOP clearance, −183% (renal, −22%)2; SN-38 +45% AUC4 | P-gp | 1.55 | 3500 | Digoxin AUC +2.8-fold1 |
CYP3A | 396 | 140 | Midazolam AUC +45% (oral), +22% (i.v.)1 | |||||||
Sulfasalazinea | 40,000 | 3- to 4-g SD7 | – | 0.46 E3S8 | 87,000 | No effect with MTX9; however, in vivo substrate10 | OATP2B1 | 311 | 13,000 | |
Regorafeniba | 1300 | 160 mg (SS)12 | – | 0.0447 TOP13 | 28,000 | No inhibition data14 | P-gp | 0.813 | 1600 | |
CYP3A4 | 22.2d,13 | 58 | ||||||||
UGT1A1 | 613 | 210 | SN-38 glucuronide AUC +44% (when coadministered with irinotecan)13 | |||||||
Curcumine | 22,000 | 2-g SD10 | 0.7 SSZ10 | 1.6 SSZ10 | 14,000 | SSZ exposure increased significantly10 | P-gp | ∼2015 | 1100 | Talinolol AUC +33%–54%17,18 |
CYP3A4 | 13.916 | 1600 | ||||||||
Erlotiniba | 1500 | 150 mg QD × 21 days19 | 0.1520 | 0.13 E3S20 | 12,000 | No effect on TOP21 | P-gp | 220 | 760 | |
OATP2B1 | 0.5511 | 2800 | ||||||||
CYP3A4 | 2.56d,22 | 600 | 2-fold increase in exposure of OSI-93025; everolimus AUC +21%26; case report of toxicity with simvastatin27 | |||||||
CYP3A5 | 80c,23 | 19 | 2-fold increase in exposure of OSI-93025; everolimus AUC +21%26; case report of toxicity with simvastatin27 | |||||||
UGT1A1 | 1.28d,24 | 1200 | No effect on irinotecan/SN-3828 | |||||||
Elacridara | 2800 | 400 mg BID × 3 days29 | – | 0.31 MIT30 | 9200 | TOP AUC +143%31 | P-gp | 0.015632 | 180,000 | Doxorubicin AUC +46%29; TOP AUC +143%31; paclitaxel AUC increased34 |
OATP2B1 | <2011 | – | ||||||||
CYP3A4 | 4.933 | 580 | ||||||||
Nilotiniba | 2800 | 400 mg BID × 15 days35 | 0.69 MTX36 | 1.38 | 2000 | No inhibition data | P-gp | 1.735 | 1700 | |
CYP3A4 | 0.437 | 7100 | Midazolam AUC +30%35 | |||||||
UGT1A1 | 0.28d,38 | 10,000 | ||||||||
Gefitiniba | 2000 | 225 mg QD × 14 days39 | – | 1.01 E3S40 | 2000 | No inhibition data | CYP3A4 | 9.6d,22 | 210 | No effect on docetaxel41 or everolimus42 |
Sunitinib | 500 | 50 mg QD × 28 days43 | 0.32 E3S44 | 0.64 | 780 | No inhibition data; in vivo substrate45 | P-gp | 15.2d,44 | 33 | Docetaxel AUC +44.7%47; case report of toxicity with colchicine48 |
CYP3A4 | 19.0d,46 | 26 | Docetaxel AUC +44.7%47 | |||||||
Pantoprazolea | 370 | 40-mg SD49 | – | 5.5 MTX50 | 67 | SSZ AUC +83.3% with 421A/C genotype51; case report of toxicity with MTX52 | P-gp | 17.953 | 21 | No effect on digoxin55,56 |
CYP3A4 | 154 | 370 | No effect on carbamazepine,57 nifedipine,58,59 or tacrolimus60 | |||||||
Rabeprazole | 440 | 40 mg QD × 8 days61 | – | 8.5 MTX50 | 52 | Delayed MTX elimination50 | CYP3A4 | 4.954 | 91 | No effect on tacrolimus62 |
BID, twice daily; CIM, cimetidine; E3S, estrone-3-sulfate; MIT, mitoxantrone; MTX, methotrexate; QD, once daily; SD, single dose; SS, dosed to steady state; SSZ, sulfasalazine; TOP, topotecan.
↵a Also present in [I1]/IC50 list.
↵b [I2] value for proposed 250-mg dose = 1000 μM.
↵c [I2]/IC50 value for proposed 250-mg dose = 40,000.
↵d IC50 value was calculated as 2 × Ki, assuming linearity.
↵e Curcumin also caused a small, but significant, decrease in the clearance of the CYP1A2 substrate caffeine (–29%) (Juan et al., 2007).
↵1 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022059s016s017lbl.pdf.
↵2 Polli et al., 2008.
↵3 Molina et al., 2008.
↵4 Midgley et al., 2007.
↵5 Sugimoto et al., 2011.
↵6 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022059s000TOC.cfm.
↵7 Goodman et al., 2001.
↵8 Elsby et al., 2011.
↵9 Haagsma et al., 1996.
↵10 Kusuhara et al., 2012.
↵11 Karlgren et al., 2012b.
↵12 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203085s001lbl.pdf.
↵13 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000TOC.cfm.
↵15 Si et al., 2013.
↵16 Appiah-Opong et al., 2007.
↵17 Juan et al., 2007.
↵18 He et al., 2012.
↵19 Yamamoto et al., 2008.
↵20 Noguchi et al., 2009.
↵21 Stewart et al., 2014.
↵22 Wang et al., 2014.
↵23 Li et al., 2010.
↵24 Liu et al., 2010.
↵25 Macpherson et al., 2013.
↵26 Bullock et al., 2011.
↵27 Veeraputhiran and Sundermeyer, 2008.
↵28 Messersmith et al., 2004.
↵29 Planting et al., 2005.
↵30 Ahmed-Belkacem et al., 2005.
↵31 Kruijtzer et al., 2002.
↵32 Dickens et al., 2013.
↵33 Englund et al., 2014.
↵34 Malingre et al., 2001.
↵35 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068TOC.cfm.
↵36 Tiwari et al., 2009.
↵37 Kenny et al., 2012.
↵38 Ai et al., 2014.
↵39 Goodman et al., 2005.
↵40 Yanase et al., 2004.
↵41 Wilding et al., 2006.
↵42 Milton et al., 2007.
↵43 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021938s024s025lbl.pdf.
↵44 Kawahara et al., 2010.
↵45 Oberoi et al., 2013.
↵46 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938s000_021968s000_Stutent.cfm.
↵47 Robert et al., 2010.
↵48 Abodunde et al., 2013.
↵49 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020987s048,022020s010lbl.pdf.
↵50 Suzuki et al., 2009.
↵51 Adkison et al., 2010.
↵52 Ranchon et al., 2011.
↵53 Pauli-Magnus et al., 2001.
↵54 Moody et al., 2013.
↵55 Hartmann et al., 1995.
↵56 Hartmann et al., 1996.
↵57 Huber et al., 1998.
↵58 Bliesath et al., 1996b.
↵59 Bliesath et al., 1996a.
↵60 Lorf et al., 2000.
↵61 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020973s032lbl.pdf.
↵62 Itagaki et al., 2004.