The sodium and calcium ionophoretic activity of meglitinide and three of its hypoglycemic analogs, namely S3075, KAD-1229 and repaglinide was examined in an artificial membrane model. All agents were able to cause the translocation of 45Ca and 22Na from an aqueous solution into an immiscible organic phase. The results were compatible with the formation of a calcium-ionophore complex with a 1-2 stoichiometry. The ionophoretic activity ranged in the following hierarchy: KAD-1229 > S3075 > repaglinide = meglitinide and, hence, did not closely parallel the insulinotropic potential of these non-sulfonylurea hypoglycemic agents. It is proposed, therefore, that the ionophoretic capacity of meglitinide analogs may not represent an essential determinant of their insulin-releasing action.