Ion pair absorption of ionized drugs--fact or fiction?

The lipophilicity of some highly ionized drugs at physiological pH is very low. Gastro-intestinal absorption of such compounds cannot be explained by the 'pH-partition' hypothesis. Ion pair formation between a drug and an endogenous counter ion alone resulting in an electrically neutral and potentially more lipophilic species has been proposed as a mechanism to explain the observed, though deficient, absorption of ionic drugs. The concept of ion pair formation between an ionic drug and an exogenous counter ion has been the rationale for attempts to improve penetration of biological membranes and, specifically, result in increased absorption from the gastro-intestinal tract. The validity of the 'ion pair absorption hypothesis' is re-evaluated in the context of a conceptual review of relevant literature.