SIGNIFICANCE OF WATER SOLUBILITY IN THE GASTROINTESTINAL ABSORPTION OF O)(1R,2R-CYCLOHEXANEDIAMINE)(OXALATO)PLATINUM(IV), AN ORALLY-ACTIVE ANTITUMOR PLATINUM COMPLEX, AND ITS ANALOGS

erato)(1R,2R-cyclohexanediamine)(oxalato)-platinum (IV)(C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absor ption of C5-OHP ws examined in rats and compared with those of C5-OHP analogs which have a general formula of s(n-OCOCnH2n+1)(1R,2R-cyclohex anediamine)(oxalato) platinum (IV) as well as C5-OHP. The complexes di d not show significant differences in pharmacokinetic behavior after i .v. injection. Plasma platinum level after a single oral administratio n at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfu sion technique was higher for a complex with higher lipophilicity. The se results indicate that the water solubility is a more dominant facto r than the lipophilicity in the gastrointestinal absorption of the com plexes. Then, the effects of surfactants and alpha-cyclodextrin (alpha -CD) on the solubility of C5-OHP was studied. Among the agents tested, alpha-CD showed the highest effect in increasing the solubility. Admi nistration of C5-OHP together with alpha-CD gave approximately three t imes higher plasma platinum levels than administration of C5-OHP alone . Water solubility was found to be a dominant factor in the gastrointe stinal absorption of C5-OHP and its analogs. [(C) 1998 Rapid Science L td.].