TABLE 7

In vitro and in vivo data and considerations for potential intestinal BCRP inhibitors

IC₅₀ and K_i values are presented as reported in the respective references, along with the substrate used.

Precipitant	[I₂]	Dose	BCRP Parameters				Other Possible Intestinal Interactions
Precipitant	[I₂]	Dose	K_i	IC₅₀	[I₂]/IC₅₀	In Vivo PK–Based DDI Data	Transporter/Enzyme	IC₅₀	[I₂]/IC₅₀	In Vivo PK–Based DDI Data
	μM		μM					μM
Lapatinib^{^a}	5300^{^b}	1250 mg QD (SS)¹	–	0.025 CIM²	210,000^{^c}	Decreased TOP clearance, −18³% (renal, −22%)²; SN-38 +45% AUC⁴	P-gp	1.5⁵	3500	Digoxin AUC +2.8-fold¹
Lapatinib^{^a}	5300^{^b}	1250 mg QD (SS)¹	–	0.025 CIM²	210,000^{^c}		CYP3A	39⁶	140	Midazolam AUC +45% (oral), +22% (i.v.)¹
Sulfasalazine^{^a}	40,000	3- to 4-g SD⁷	–	0.46 E3S⁸	87,000	No effect with MTX⁹; however, in vivo substrate¹⁰	OATP2B1	3¹¹	13,000
Regorafenib^{^a}	1300	160 mg (SS)¹²	–	0.0447 TOP¹³	28,000	No inhibition data¹⁴	P-gp	0.8¹³	1600
							CYP3A4	22.2^{^d}^,¹³	58
							UGT1A1	6¹³	210	SN-38 glucuronide AUC +44% (when coadministered with irinotecan)¹³
Curcumin^{^e}	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
Curcumin^{^e}	22,000	2-g SD¹⁰	0.7 SSZ¹⁰	1.6 SSZ¹⁰	14,000	SSZ exposure increased significantly¹⁰	CYP3A4	13.9¹⁶	1600
Erlotinib^{^a}	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	2.56^{^d}^,²²	600	2-fold increase in exposure of OSI-930²⁵; everolimus AUC +21%²⁶; case report of toxicity with simvastatin²⁷
							CYP3A5	80^{^c}^,²³	19	2-fold increase in exposure of OSI-930²⁵; everolimus AUC +21%²⁶; case report of toxicity with simvastatin²⁷
							UGT1A1	1.28^{^d}^,²⁴	1200	No effect on irinotecan/SN-38²⁸
Elacridar^{^a}	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
Nilotinib^{^a}	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	0.28^{^d}^,³⁸	10,000
Gefitinib^{^a}	2000	225 mg QD × 14 days³⁹	–	1.01 E3S⁴⁰	2000	No inhibition data	CYP3A4	9.6^{^d}^,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	15.2^{^d}^,⁴⁴	33	Docetaxel AUC +44.7%⁴⁷; case report of toxicity with colchicine⁴⁸
Sunitinib	500	50 mg QD × 28 days⁴³	0.32 E3S⁴⁴	0.64	780	No inhibition data; in vivo substrate⁴⁵	CYP3A4	19.0^{^d}^,⁴⁶	26	Docetaxel AUC +44.7%⁴⁷
Pantoprazole^{^a}	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
Pantoprazole^{^a}	370	40-mg SD⁴⁹	–	5.5 MTX⁵⁰	67		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 × K_i, 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.
↵¹⁴ https://clinicaltrials.gov/show/NCT02106845.
↵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.