Received for publication September 14, 2005.
Revised October 24, 2005.
Accepted for publication November 2, 2005.

Evaluation of inhibitory potencies for compounds inhibiting P-glycoprotein but without maximum effects: f2-values

Abstract

In cell culture systems with aqueous buffers concentration-response curves to lipophilic inhibitors are difficult to establish because plateau effects (I_max) are often not reached due to limited drug solubility. Consequently, the inhibitory potency of a compound will not be definable using IC₅₀-values (concentration exerting 50% of I_max). As alternative potency measures f2-values, the concentrations required to double baseline signals, have been proposed. Using both methods we reevaluated the concentration-response curves of calcein assays with 78 compounds in 3 different cell culture systems and found a close correlation between both methods (r_s = 0.93-0.99, p<0.0028). These findings suggest that f2-values are a valuable alternative to define rank orders of highly lipophilic inhibitors as a basis for the prediction of pharmacological interaction properties in clinical settings. Although only tested for inhibition of P-glycoprotein it appears likely that this method may be transferred to other assays with other proteins.

Key words: ABC transporters, drug efflux, drug interactions, drug transport, drug-drug interactions, in vitro-in vivo prediction, p-glycoprotein

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