Antitumour and Pharmacokinetic Studies with Platinum Coordination Complexes Following Oral Administration
Cisplatin and its analogues, cis-diammine(1,1-cyclobutanedicarboxy lato)platinum II (CBDCA, JM8) and cis-dichloro-trans-dihydroxy-bis(isopropylamine)platinum IV (CHIP, JM9), are active against a number of experimental rodent neoplasms when administered parenterally. This is the first report to describe the antitumour activity of this class of compounds following oral administration via a stomach tube. The complexes were tested against the ADJ/PC6A plasmacytoma grown s.c. in female Balb C- mice, and the Walker 256 carcinosarcoma grown i.m. in male Wistar rats. Cisplatin had a TI (therapeutic index; LD50/ED90) of 4–5 against the ADJ/PC6A and a TI of 2 against the Walker 256. Comparable or lower activity against the ADJ/PC6A has also been demonstrated for CBDCA and CHIP. Following an oral dose of 50mg/kg in mice of the three complexes, maximum platinum levels in blood (1.5–2.4µg/ml) are achieved 1–4 hours after drug administration. Urinary excretion is greatest for cisplatin (15% of dose in 48 hours), followed by CHIP (13%) and CBDCA (9%). The major part (60–80&) of the dose, however, is excreted in the faeces. These results indicate that the orally administered cisplatin and the two analogues are absorbed to an appreciable extent into the systemic circulation. This is probably important in producing the observed antitumour activities of the complexes when given by this route of administration.