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The relevance of assessment of intestinal P-gp inhibition using digoxin as an in vivo probe substrate

Nature Reviews Drug Discovery volume 10, page 75 (2011)Cite this article

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The recent Review (Membrane transporters in drug development. Nature Rev. Drug Discov. 9, 215–236; 2010)1 by the International Transporter Consortium (ITC) proposed that, for a new molecular entity (NME) intended for oral administration, a clinical drug interaction study with digoxin should be conducted if [I2]/IC50 ≥ 10 (where I2 is the hypothetical concentration of the NME in gut lumen, and IC50 is the NME's potency of P-glycoprotein (P-gp) inhibition in vitro). However, the Review does not adequately address the choice of digoxin as a suitable in vivo P-gp probe substrate in the context of digoxin's clinical pharmacokinetics, as well as the prevalence of drug–drug interactions due to inhibition of P-gp at the intestinal level and hence the importance of such interactions.

Digoxin is certainly a sensitive probe substrate of P-gp in in vitro studies, as evidenced by a high efflux ratio across Caco-2, MDR1-MDCK and MDR1-LLCPK1 cells, as well as effective inhibition of efflux in the presence of P-gp inhibitors. However, the in vivo situation is less clear. In humans, digoxin is subjected to minimal metabolism and its oral bioavailability approximates its fraction absorbed in the gastrointestinal tract. Administered in standard tablet formulation, digoxin exhibits good but incomplete absorption; for example, the absolute bioavailability of Lanoxin (GlaxoSmithKline) is 60–80% (Ref. 2). When dosed in solubilized formulations (for example, Lanoxicaps), digoxin is almost completely absorbed2,3, which questions the relevance of P-gp-mediated efflux in the oral absorption of digoxin. Other reports support the notion that the rate of oral absorption of digoxin is limited by dissolution (rather than permeability)4,5. It should also be noted that grapefruit juice, an intestinal P-gp inhibitor, has a non-significant effect on digoxin serum concentrations6, and ketoconazole — a potent P-gp inhibitor — is not known to cause significant interaction with digoxin, which further undermines the choice of digoxin as an in vivo probe substrate.

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  1. Jack G. Shi, Yan Zhang and Swamy Yeleswaram are at Incyte Corporation, Wilmington, Delaware, USA.,

    Jack G. Shi, Yan Zhang & Swamy Yeleswaram

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Correspondence to Swamy Yeleswaram.

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Shi, J., Zhang, Y. & Yeleswaram, S. The relevance of assessment of intestinal P-gp inhibition using digoxin as an in vivo probe substrate. Nat Rev Drug Discov 10, 75 (2011). https://doi.org/10.1038/nrd3028-c1

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