TRANSIENT ENTEROHEPATIC CIRCULATION AND ENHANCED BILIARY VERSUS URINARY-EXCRETION OF THE CYTOSTATIC DRUG BISCHOLYLGLYCINATE-CHLOROPLATINUM(II) (BAMET-H2)

Using intraluminal perfusion of ''in situ'' ileum in anaesthetized rat s bearing catheters into the portal vein and the common bile duct that permitted portal blood and bile sample collection, and in conscious r ats in which a permanent intraarterial catheter had been implanted to carry out sequential blood sampling, the existence of enterohepatic ci rculation of the cytostatic drug Bamet-H2-Na[Pt(cholylgycinate-O,N) (c holylgycinate-O) Cl]-was investigated. Total platinum in serum, bile, ileum, liver, urine and feces was measured by flameless atomic absorpt ion spectroscopy. After i.v. and i.g., 1 mu mol Bamet-H2 or cisplatin administration, model-independent methods based on the theory of stati stical moments were used in order to characterize the pharmacokinetics of Bamet-H2. The area under the curve from 0 to 168 h after i.v. admi nistration (AUC(168)) was significantly higher (+ 27%) for Bamet-H2 th an for cisplatin. However, extrapolation from 0 to infinity indicated that AUC(infinity) was lower for Bamet-H2 (- 23%) than for cisplatin. The clearance (Cl-infinity) for cisplatin was consistently lower (-23% ) than for Bamet-H2. Ultrafiltration of serum collected at 168 h revea led that an important part of the Bamet-H2 (67%) and cisplatin (53%) r emaining in the serum at this time was in the nonultrafiltrable form, i.e. probably bound, in part irreversibly, to serum macromolecules. Wh en the rats received i.g. 1 mu mol cisplatin or Bamet-H2, peak in seru m concentrations of total platinum were markedly higher (6-fold) after Bamet-H2 than after cisplatin administration. The area under the curv e was, also in this case, significantly higher for Bamet-H2 than for c isplatin (+ 98%). This was in part due to the enhanced intestinal abso rption of Barnet-H2, as confirmed in experiments on perfused rat ileum , where an increase in portal serum Bamet-H2 concentrations was found. Moreover, markedly higher amount of the drug was found in ileum, live r and bile after perfusion with media containing Bamet-H2 as compared with experiments where cisplatin instead of Bamet-H2 was added to perf usion media. Moreover, after i.v. administration to conscious rats, ex cretion of Bamet-H2 by the kidney was lower (- 51%) than that of cispl atin, while elimination of the former compound into feces was higher ( +189%) than that of the latter. In sum, these results indicate that in addition to the previously reported cytostatic activity of Bamet-H2, this complex has interesting cholephilic characteristics, such as redu ced urinary excretion together with enhanced intestinal absorption and biliary secretion, which are probably endowed by one or both cholylgl ycyl moieties bound to the platinum(II) atom in the Bamet-H2 molecule. (C) 1998 Elsevier Science B.V. All rights reserved.