Summary of the ADME properties, in vitro passive permeability, in vitro BCRP substrate properties, and details of preclinical and clinical PK studies for drugs associated with BCRP interaction

DrugGeneral ADME-PK PropertiesaPassive Permea-bility bBCRP Substrate In VitroPK Changes in Bcrp1(−/−) MicePK Changes in BCRP Pharmacogenetic Clinical StudiesPK Changes in Clinical DDI Studies
Methotrexate (chemotherapy)MDR1, OATs, and aldehyde oxidase substrate (Norris et al., 1996)LowcY (Poguntke et al., 2010)1.7-fold increase in AUC (Vlaming et al., 2011)Impact on PD (psoriasis patients), no toxicity, no information on PK (Warren et al., 2008)Delayed elimination + severe intoxication (+dual MDR1/BCRP inhibitors: omeprazole, pantoprazole; Santucci et al., 2010)
F ∼70%
Low therapeutic window
Sulfasalazine (inflammatory bowel diseases)Bacterial azoreductase substrate (Yamasaki et al., 2008)LowcY (Urquhart et al., 2008)111-fold increase in AUC (Zaher et al., 2006)c.34GG and c.421AA/CC/CA: <2- to 4-fold AUC increases; inconsistent findings between studies (Adkison et al., 2010; Schnepf and Zolk, 2013)No significant association with PK (+dual MDR1/BCRP inhibitor: pantoprazole) (Adkison et al., 2010); 3.2 max fold AUC increase (+BCRP and enzymes inhibitor: curcumin) (Kusuhara et al., 2012)
OATP2B1 substrate (Kusuhara et al., 2012)
F∼3–12%/high protein binding
Statins (hyperlipidemia): all good OATP substrates (Poirier et al., 2007)
 RosuvastatinMinor role of metabolismLowcY (Hirano et al., 2005)2-fold decrease in total plasma CL (Kitamura et al., 2008)c.421CA/AA: 2- to 2.4-fold AUC increases (Zhang et al.,. 2006 ;Ieiri et al., 2009; Keskitalo et al., 2009b)1.6 max fold AUC increase (+ dual OATP/BCRP inhibitors: eltrombopag, ritonavir) (Allred et al., 2011); 7-fold increase (+multiple transporters and enzymes inhibitor: CsA) (Schnepf and Zolk, 2013)
F ∼10–20%
 AtorvastatinCYP3A4 substrateLowcBorderline (Keskitalo et al., 2009b)NRc.421AA: 1.7-fold AUC increase (Keskitalo et al., 2009b)NR
F ∼12%
 FluvastatinMDR1c and CYP2C9 substrate - extensive metabolism and biliary excretionLowcY (Hirano et al., 2005; Xia et al., 2005)NRc.421AA: 2-fold AUC increase (Keskitalo et al., 2009a)NR
F ∼29% / high protein binding
 Simvastatin lactoneCYP3A4 (major) & 2C8 substrate – significant metabolismMediumcY (Xia et al., 2005)NRc.421AA: 2.1-fold AUC increase (Keskitalo et al., 2009a)NR
F ∼5%
 PitavastatinMDR1 substratecMediumcY (Hirano et al., 2005)No impact on total plasma CL/10-fold decrease in biliary excretion clearance (Hirano et al., 2005)c.421AA/CC/CA: no significant association with PK (Ieiri et al., 2007)NR
Minor role of metabolism
F ∼50%
 PravastatinMinor role of metabolismLow (Caco2; Marino et al., 2005)Y (Hirano et al., 2005)NRc.421AA/CC/CA: no significant association with PK (Keskitalo et al., 2009a)NR
Tyrosine kinase inhibitors (chemotherapy)
 GefitinibMDR1 substratecMediumcY (Xia et al., 2005; Li et al., 2007)No impact on brain distribution (Agarwal et al., 2010)c.421CA 1.4-fold increase of Ctrough no impact on AUC or Cmax (Li et al., 2007)NR
Extensive metabolism by CYP3A54 (major) and CYP2D6
F ∼60%
 SunitinibMDR1c and CYP3A4/5 substrateMediumcY (Tang et al., 2012)3.7-fold increase in AUC (Mizuno et al., 2012); no impact on plasma exposure but on brain distribution (Tang et al., 2012; Schnepf and Zolk, 2013)c.421CA/AA 1.7- to 3-fold AUC increase (Mizuno et al., 2012)NR
F unknown
 ImatinibMDR1c and CYP3A4/5 substrateHigh aY (Xia et al., 2005)No impact on plasma exposure but on brain distribution (Schnepf and Zolk, 2013)c.421CA: no significant association with PK (Gardner et al., 2006)NR
F ∼100%
Camptothecins (chemotherapy)
 IrinotecanMDR1 substratecLowcY (Xia et al., 2005)NRc.421CA, c.34GA: no significant association with PK – some report of related myelosuppression (Meyer zu Schwabedissen and Kroemer, 2011)NR
considered as a prodrug (of SN-38), carboxylesterases substrate
 TopotecanMDR1 substratecLowcY (Xia et al., 2005)3.6-fold increase in AUC (Yamagata et al., 2007)c.421CA: increase in F from ∼30% to ∼40%, no significant change in AUC, very small sample size (Sparreboom et al., 2005)Increase in F from ∼40% to ∼100% (+dual MDR1 / BCRP inhibitor: elacridar) (Schnepf and Zolk, 2013)
F∼40% (Gelderblom et al., 2003)
Not extensively metabolized (Schnepf and Zolk, 2013)
  • ADME, absorption, distribution, metabolism, and elimination; CL, clearance; F, apparent oral bioavailability in humans; NR, not reported; Y, substrate (yes).

  • a From Benet et al., (1996) and if not stated otherwise.

  • b Low: <30 nm/s; medium: 30–100 nm/s; high: >100 nm/s.

  • c: Data from L-MDR1 cells in the presence of inhibitor (Poirier et al., 2014).