title: Significance of water solubility in the gastrointestinal absorption of trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)platinum(IV), an orally active antitumor platinum complex, and its analogs.
abstract: Trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato++ +)platinum(IV) (C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absorption of C5-OHP was examined in rats and compared with those of C5-OHP analogs which have a general formula of trans-bis(n-OCOCnH2n+1)(1R,2R-cyclohexanediamine)(oxalato )platinum(IV) as well as C5-OHP. The complexes did not show significant differences in pharmacokinetic behavior after i.v. injection. Plasma platinum level after a single oral administration at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfusion technique was higher for a complex with higher lipophilicity. These results indicate that the water solubility is a more dominant factor than the lipophilicity in the gastrointestinal absorption of the complexes. 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. Administration of C5-OHP together with alpha-CD gave approximately three times higher plasma platinum levels than administration of C5-OHP alone. Water solubility was found to be a dominant factor in the gastrointestinal absorption of C5-OHP and its analogs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kizu
authors.forename: T
authors.initials: T
authors.lastname: Nakanishi
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Hayakawa
authors.forename: A
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: M
authors.initials: M
authors.lastname: Eriguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: N
authors.initials: N
authors.lastname: Akiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Kidani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003505:Cyclodextrins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood; D011355:Prodrugs / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013501:Surface-Active Agents / Q000493:pharmacokinetics; D047391:alpha-Cyclodextrins
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D009944:Organoplatinum Compounds; D011355:Prodrugs; D013501:Surface-Active Agents; D047391:alpha-Cyclodextrins; C105372:bis-valerato-oxalato-1,2-diaminocyclohexaneplatinum; D010984:Platinum; C032613:alpha-cyclodextrin