PENTOXIFYLLINE - ITS PHARMACOKINETICS AND ABILITY TO IMPROVE TUMOR PERFUSION AND RADIOSENSITIVITY IN MICE

The pharmacokinetics of pentoxifylline and its three major metabolites were measured after intraperitoneal administration of 10 mg/g or 100 mg/kg of drug in C3H mice. Peak concentrations of pentoxifylline were approximately 10 and 100 mug/ml, respectively, with elimination half-l ives (+/- 2 SE) of 4.6 (4.2-5.1) and 7.5 (7.2-7.9) min, respectively. Plasma concentrations of the pharmacologically active hydroxy metaboli te were approximately one-tenth those of the parent compound. In vitro evidence of the ability of pentoxifylline to increase blood cell defo rmability indicates that concentrations of up to 30 mug/ml can increas e deformability of both red and white blood cells; doses between 5 mg/ kg and 100 mg/kg were therefore tested 15 min after administration to test the effect of the drug on tumour and normal tissue perfusion, tum our radiosensitivity and renal function immediately after exposure to appropriate drug concentrations. Using Rb-86 extraction, doses of 10-1 00 mg/kg pentoxifylline were shown to increase relative tumour perfusi on of the RIF-1 tumour to 140-170% of control, with no effect in skin, muscle, kidney, liver or lung, but with similar increases in spleen p erfusion; there was no significant effect in any tissue after 5 mg/kg. Using a clonogenic assay, this increased tumour perfusion was shown t o be reflected in increased tumour radiosensitivity to 25 Gy 15 min af ter pentoxifylline, with the same dose threshold of 10 mg/kg, and simi lar lack of dose-dependence at higher doses; the response indicated re duction in hypoxic fraction by a factor of 2-3. Renal function, measur ed by [Cr-51]EDTA and, [I-125]iodohippurate clearance was unaffected a t doses up to 50 mg/kg, with a slight effect at 100 mg/kg. The data in dicate that pentoxifylline is effective at increasing relative tumour perfusion, with minimal effects on other tissues, and this increase is reflected in improved radiosensitivity. The doses at which the drug i s effective are compatible with the mechanism being modification of bl ood cell deformability. Pentoxifylline shows promise as a clinical rad iosensitiser acting by direct increase in tumour oxygenation.