Cholephilic characteristics of a new cytostatic complex of cisplatin with glycocholate (Bamet-R2)

The aim of this work was to investigate both the existence of enterohepatic circulation of cisplatin-cholylglycinate complex, Bamet-R2, and the releva nce of biliary versus urinary excretion of this compound. Two experimental models were used: (i) intraluminal perfusion of 'in situ' ileum in anaesthe tized rats bearing a biliary catheter that permitted bile sample collection and (ii) conscious rats in which a permanent intraarterial catheter had be en implanted to carry out sequential blood sampling after intravenous (i.v. ) or intragastric (i.g.) drug administration. Total platinum in serum, bile , ileum, liver, urine and feces was measured by flameless atomic absorption spectroscopy. Serum concentration versus time curves obtained after i.v. a dministration of 1 mu mol Bamet-R2 or cisplatin revealed that the area unde r the curve was significantly higher for Bamet-R2 than for cisplatin (+48%) . Non-ultrafiltrable platinum accounted for 54.8 and 48.4% of serum platinu m 168 h after cisplatin and Bamet-R2 i.v. administration, respectively. Whe n the animals received i.g. 1 mu mol cisplatin or Bamet-R2, serum concentra tions of total platinum were markedly higher (three-fold) after Bamet-R2 th an after cisplatin administration. The area under the curve was, also in th is case, significantly higher for Bamet-R2. than for cisplatin (+28%). This was in part due to the enhanced intestinal absorption of Bamet-R2, as conf irmed in experiments on perfused rat ileum, where a markedly higher amount of the drug was found in ileum tissue and bile after perfusion with media c ontaining Bamet-R2 as compared with experiments where cisplatin instead of Bamet-R2 was added to perfusion media. Moreover, after i.v. administration to conscious rats, excretion of Bamet-R2 by the kidney was three-fold lower than that of cisplatin, while elimination of the former compound into fece s was four-fold higher than that of the latter. In summary, these results i ndicate that in addition to the previously reported cytostatic activity of Bamet-R2, this complex has interesting cholephilic characteristics typical of bile acids, such as low urinary excretion together with enhanced intesti nal absorption and biliary secretion, probably endowed by the cholylglycyl moiety included in the Bamet-R2 molecule. (C) 1999 Elsevier Science B.V. Al l rights reserved.