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
| Drug | General ADME-PK Propertiesa | Passive Permea-bility b | BCRP Substrate In Vitro | PK Changes in Bcrp1(−/−) Mice | PK Changes in BCRP Pharmacogenetic Clinical Studies | PK Changes in Clinical DDI Studies |
|---|---|---|---|---|---|---|
| Methotrexate (chemotherapy) | MDR1, OATs, and aldehyde oxidase substrate (Norris et al., 1996) | Lowc | Y (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) | Lowc | Y (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) | ||||||
| Rosuvastatin | Minor role of metabolism | Lowc | Y (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% | ||||||
| Atorvastatin | CYP3A4 substrate | Lowc | Borderline (Keskitalo et al., 2009b) | NR | c.421AA: 1.7-fold AUC increase (Keskitalo et al., 2009b) | NR |
| F ∼12% | ||||||
| Fluvastatin | MDR1c and CYP2C9 substrate - extensive metabolism and biliary excretion | Lowc | Y (Hirano et al., 2005; Xia et al., 2005) | NR | c.421AA: 2-fold AUC increase (Keskitalo et al., 2009a) | NR |
| F ∼29% / high protein binding | ||||||
| Simvastatin lactone | CYP3A4 (major) & 2C8 substrate – significant metabolism | Mediumc | Y (Xia et al., 2005) | NR | c.421AA: 2.1-fold AUC increase (Keskitalo et al., 2009a) | NR |
| F ∼5% | ||||||
| Pitavastatin | MDR1 substratec | Mediumc | Y (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% | ||||||
| Pravastatin | Minor role of metabolism | Low (Caco2; Marino et al., 2005) | Y (Hirano et al., 2005) | NR | c.421AA/CC/CA: no significant association with PK (Keskitalo et al., 2009a) | NR |
| Tyrosine kinase inhibitors (chemotherapy) | ||||||
| Gefitinib | MDR1 substratec | Mediumc | Y (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% | ||||||
| Sunitinib | MDR1c and CYP3A4/5 substrate | Mediumc | Y (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 | ||||||
| Imatinib | MDR1c and CYP3A4/5 substrate | High a | Y (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) | ||||||
| Irinotecan | MDR1 substratec | Lowc | Y (Xia et al., 2005) | NR | c.421CA, c.34GA: no significant association with PK – some report of related myelosuppression (Meyer zu Schwabedissen and Kroemer, 2011) | NR |
| F∼10% | ||||||
| considered as a prodrug (of SN-38), carboxylesterases substrate | ||||||
| Topotecan | MDR1 substratec | Lowc | Y (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 http://www.druginteractioninfo.org 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).