Liver organotropism and biotransformation of a novel platinum-ursodeoxycholate derivative, Bamet-UD2, with enhanced antitumour activity

Background/aims Several members of a novel family of bile acid derivatives with cytostatic and virostatic activity have been synthesized and character ized. The aim of this work was to investigate the liver organotropism and b iotransformation of two novel compounds with enhanced DNA-reactivity: Bamet -D3, in which a glycine-polyamine tandem was used as a spacer to separate t he glycocholic acid moiety from the platinum(II) atom, and Bamet-UD2, in wh ich cisplatin was directly bound to the carboxylate group of two ursodeoxyc holic acid moieties. Methods Drug uptake and "in vitro" toxicity were investigated using rat hep atocytes in primary culture. Following i.v. administration of 0.5 mu mol ci splatin, Bamet-D3 or Bamet-UD2, bile output, urinary and fecal excretion., organ distribution and pharmacokinetic parameters were determined in short- term (3 h) and long-term (14 days) experiments carried out on anaesthetized and conscious rats, respectively. Liver biotransformation was investigated by HPLC analysis of bile samples, Total platinum was measured by flameless atomic absorption spectroscopy. Using Nude mice, antitumour activity was i nvestigated in subcutaneously implanted Hepa 1-6 mouse hepatoma cells. Results Uptake by rat hepatocytes was Bamet-UD2 (11.3 nmol/mg protein)> Bam et-D3 (5.6 nmol/mg protein)> cisplatin (2.1 pmol/mg protein). Bamet-UD2 ind uced "in vitro" cell toxicity, which was not observed for Bamet-D3 or cispl atin. On the contrary, no toxicity "in vivo" for Bamet-UD2 was found which was observed for cisplatin and Bamet-D3. This may be related with the fact that bile output of Bamet-UD2, which occurs with no major biotransformation , was > 10 fold higher than that of cisplatin and 3-fold higher than that o f Bamet-D3, which was previously transformed into at least three different metabolites. Fecal excretion was Bamet-UD2 > Bamet-D3 > cisplatin, whereas urinary output was Bamet-B3 > cisplatin > Bamet-UD2. Accordingly, a marked liver- and a reduced kidney-vectoriality for Bamet-UD2, but not for Bamet-D 3, was observed. Bamet-UD2 and cisplatin, but not Bamet-D3, were efficient in inhibiting tumour growth whereas, only Bamet-UD2 significantly prolonged survival time. Conclusions These results indicate that Bamet-UD2 is a cisplatin-ursodeoxyc holate derivative with strong antitumour activity, marked hepatobiliary org anotropism, and reduced toxic side-effects as compared to the parent drug c isplatin.