The oral absorption of iothalamate and the effect of amino acids on its absorption were studied in 6 dogs and 6 rats using a simple HPLC assay. The results showed that iothalamate was absorbed in dogs. averaging 9.9, 8.5. and 10.0 per cent following the administration of 40 and 100mg kg-' of iothalamic acid capsules and 50mg kg-' of sodium iothalamate solution, respectively. The absorption from the capsule was slower and more sustained than that from the solution. In rats, the absorption appeared to be dose-independent (averaging about 4.2 per cent) in the dose range of 2&800mg kg-'. The low bioavailability obtained was mainly due to the high polarity of iothalamate molecules as suggested by the GI recovery and in vitro partition studies. Among several amino acids tested as possible ion-pair formers, only homoarginine hydrochloride increased the partition of iothalamate into chloroform layer. However, both homoarginine hydrochloride and arginine hydrochloride at the amino acidhothalamate molar ratio of 25 were found to significantly enhance (about 70 per cent) the iothalamate absorption in dogs. The in situ rat small intestinal loop study indicated that the absorption-enhancing effect of arginine was sodium dependent. At the sodium chloride concentration of 0.09 M, no significant increase in the absorption was observed, while at the concentration of 0.3 M or higher, a marked increase (about twofold) was obtained in both upper and lower intestine. Thus, the mechanism of the amino acids in facilitating the iothalamate absorption may be more closely related to the active amino acid transport system rather than the possible increase in lipophilicity of the ion-pair formed. The potential use of such naturally occurring, relatively non-toxic amino acids for increasing the GI absorption of water-soluble weak acids or bases through ion-pair formation remains to be fully investigated.