PHARMACOKINETICS AND BINDING OF THE BIOREDUCTIVE PROBE FOR HYPOXIA, NITP - EFFECT OF ROUTE OF ADMINISTRATION

The novel compound 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (N ITP) can be used as an immunologically detectable probe for hypoxic ce lls. Because of the limited water solubility of NITP, it has been admi nistered dissolved in peanut oil with 10% dimethylsulphoxide (DMSO). A new aqueous formulation has been devised, based on a 50% solution of a modified B-cyclodextrin (Molecusol HPB), which increases the water s olubility of MTP 10-fold. The pharmacokinetics of NITP in plasma and t umours have been compared following oral and intraperitoneal (i.p.) ad ministration of the NITP in Molecusol, i.p. administration of NITP dis solved in peanut oil + 10% DMSO and injection of a near-saturated aque ous solution of the drug intravenously via the tail vein or i.p. or di rectly into the tumours. Binding of the marker to hypoxic cells within rumours was also measured after the different routes of administratio n. The Molecusol vehicle was unexpectedly toxic when administered i.p. , but there was no toxicity from NITP dissolved in Molecusol when admi nistered orally. Binding of the drug within tumours was seen for both the peanut oil + 10% DMSO and Molecusol formulations and for both oral and intraperitoneal routes. Binding of NITP within tumours has also b een observed following direct injection of the drug, with minimal whol e-body exposure to NITP. However, the bound metabolites of NITP within tumours were localised to the injection site, suggesting that direct injection is unlikely to be a useful method of administering bioreduct ive hypoxia markers. The data in this paper demonstrate that bound met abolites of the hypoxia marker NITP can be detected in tumours followi ng oral administration of an aqueous formulation of NITP, and suggest that oral administration could be a satisfactory administration route for clinical studies with MTP.