title: Cholephilic characteristics of a new cytostatic complex of cisplatin with glycocholate (Bamet-R2).
abstract: The aim of this work was to investigate both the existence of enterohepatic circulation of cisplatin-cholylglycinate complex, Bamet-R2, and the relevance of biliary versus urinary excretion of this compound. Two experimental models were used: (i) intraluminal perfusion of 'in situ' ileum in anaesthetized rats bearing a biliary catheter that permitted bile sample collection and (ii) conscious rats in which a permanent intraarterial catheter had been 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. administration of 1 micromol Bamet-R2 or cisplatin revealed that the area under the curve was significantly higher for Bamet-R2 than for cisplatin (+48%). Non-ultrafiltrable platinum accounted for 54.8 and 48.4% of serum platinum 168 h after cisplatin and Bamet-R2 i.v. administration, respectively. When the animals received i.g. 1 micromol cisplatin or Bamet-R2, serum concentrations of total platinum were markedly higher (three-fold) after Bamet-R2 than after cisplatin administration. The area under the curve was, also in this case, significantly higher for Bamet-R2 than for cisplatin (+28%). This was in part due to the enhanced intestinal absorption of Bamet-R2, as confirmed 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 containing 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 feces was four-fold higher than that of the latter. In summary, these results indicate 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 intestinal absorption and biliary secretion, probably endowed by the cholylglycyl moiety included in the Bamet-R2 molecule.
authors.affiliation: Departments of Physiology-Pharmacology, University of Salamanca, 37007-Salamanca, Spain.
authors.forename: R I
authors.initials: RI
authors.lastname: Macias
authors.forename: M Y
authors.initials: MY
authors.lastname: El-Mir
authors.forename: M J
authors.initials: MJ
authors.lastname: Monte
authors.forename: M A
authors.initials: MA
authors.lastname: Serrano
authors.forename: M J
authors.initials: MJ
authors.lastname: Garcia
authors.forename: J J
authors.initials: JJ
authors.lastname: Marin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D006000:Glycocholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010477:Perfusion; D010984:Platinum / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D013054:Spectrophotometry, Atomic