Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies

Mol Pharm. 2010 Apr 5;7(2):398-411. doi: 10.1021/mp900174z.


The objective of this work was to further investigate the reasons for disconcordant clinical digoxin drug interactions (DDIs) particularly for false negative where in vitro data suggests no P-glycoprotein (P-gp) related DDI but a clinically relevant DDI is evident. Applying statistical analyses of binary classification and receiver operating characteristic (ROC), revised cutoff values for ratio of [I]/IC(50) < 0.1 and [I(2)]/IC(50) < 5 were identified to minimize the error rate, a reduction of false negative rate to 9% from 36% (based on individual ratios). The steady state total C(max) at highest dose of the inhibitor is defined as [I] and the ratio of the nominal maximal gastrointestinal concentration determined for highest dose per 250 mL volume defined [I(2)](.) We also investigated the reliability of the clinical data to see if recommendations can be made on values that would allow predictions of 25% change in digoxin exposure. The literature derived clinical digoxin interaction studies were statistically powered to detect relevant changes in exposure associated with digitalis toxicities. Our analysis identified that many co-meds administered with digoxin are cardiovascular (CV) agents. Moreover, our investigations also suggest that the presence of CV agents may alter cardiac output and/or kidney function that may act alone or are additional components to enhance digoxin exposure along with P-gp interaction. While we recommend digoxin as the probe substrate to define P-gp inhibitory potency for clinical assessment, we observed high concordance in P-gp inhibitory potency for calcein AM as a probe substrate.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Clinical Trials as Topic
  • Digoxin / metabolism*
  • Drug Interactions*
  • Humans
  • Inhibitory Concentration 50
  • Pharmaceutical Preparations / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Pharmaceutical Preparations
  • Digoxin