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Drug–Drug Interactions Mediated Through P‐Glycoprotein: Clinical Relevance and In Vitro – In Vivo Correlation Using Digoxin as a Probe Drug
Author(s) -
Fenner KS,
Troutman MD,
Kempshall S,
Cook JA,
Ware JA,
Smith DA,
Lee CA
Publication year - 2009
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.195
Subject(s) - drug , digoxin , in vivo , pharmacology , medicine , in vitro , chemistry , biology , heart failure , biochemistry , microbiology and biotechnology
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, ≤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 ). Clinical Pharmacology & Therapeutics (2009); 85 , 2, 173–181 doi: 10.1038/clpt.2008.195