Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug.
The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, <or=100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P-gp, because of the absence of metabolic clearance. In vitro inhibitory potency data (concentration of inhibitor to inhibit 50% P-gp activity; IC(50)) were generated using Caco-2 cells for 19 P-gp inhibitors. Maximum steady-state inhibitor systemic concentration [I], [I]/IC(50) ratios, hypothetical gut concentration ([I(2)], dose/250 ml), and [I(2)]/IC(50) ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (C(max))(,i,ss)/C(max,ss) and area under the curve (AUC)(i)/AUC ratios from the clinical trials. [I]/IC(50) < 0.1 shows high false-negative rates (24% AUC, 41% C(max)); however, to a limited extent, [I(2)]/IC(50) < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC(50) > 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).
Fenner
K S
KS
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, Sandwich, UK.
Troutman
M D
MD
Kempshall
S
S
Cook
J A
JA
Ware
J A
JA
Smith
D A
DA
Lee
C A
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000638:Amiodarone / Q000378:metabolism / Q000494:pharmacology; D018938:Caco-2 Cells; D004077:Digoxin / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012189:Retrospective Studies
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D004077:Digoxin; D000638:Amiodarone