P-gp inhibition interactions, in vitro to in vivo translation

PerpetratorIn Vitro SubstrateIC50[I]1/IC50[I]2/IC50AUC RatioCmax RatioIn Vivo VictimReference
AlectinibN/P1.11.2a,b4521a,bN/TcFDA (2015b)
Alectinib metabolite M4N/P4.70.1N/A
BrexpiprazoleDigoxin6.310.07a5.85a1.04FexofenadineFDA (2015v)
Brexpiprazole metabolite DM-3411Digoxin7.840.018N/A
CariprazineN/PWeak (value N/P)N/AN/TFDA (2015zd)
Cariprazine metabolite DCARN/PWeak (value N/P)N/A
Cariprazine metabolite DDCARN/PWeak (value N/P)N/A
DaclatasvirDigoxin4.40.53a,b74a,b1.271.65DigoxinFDA (2015j)
EdoxabanN/PNo inhibitionN/ANo effect (value N/P)DigoxinFDA (2015w)
FlibanserinDigoxinWeak (value N/P)N/A1.931.46DigoxinFDA (2015a)
Isavuconazonium sulfateN/P25.70.67a,b71a,b1.251.33DigoxinFDA (2015i)
IvabradineN/PNo inhibitionNo effect (value N/P)DigoxinFDA (2015g)
Ivabradine metabolite S18982N/P5.3≤0.1N/A
LesinuradN/P10000.021.98aN/TFDA (2015zg)
RolapitantDigoxin7.360.23a,b196a,b1.271.67DigoxinFDA (2015za)
SacubitrilRhodamine 123No inhibitionNo effect (value N/P)DigoxinFDA (2015k)
Uridine triacetateDigoxin344N/Ad108a,bN/TFDA (2015ze)
  • N/A, not applicable; N/P, not provided; N/T, not tested.

  • a The ratio was calculated by the University of Washington Drug Interaction Database editorial team.

  • b Values exceed the FDA cut-off value of 0.1 ([I]1/IC50) or 10 ([I]2/IC50).

  • c A clinical study was recommended in the comments by the FDA reviewers.

  • d Uridine triacetate is rapidly converted to uridine, and therefore has a low systemic circulation; uridine did not inhibit P-gp in vitro.