Pentoxifylline: its pharmacokinetics and ability to improve tumour 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 micrograms/ml, respectively, with elimination half-lives (+/- 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 metabolite were approximately one-tenth those of the parent compound. In vitro evidence of the ability of pentoxifylline to increase blood cell deformability indicates that concentrations of up to 30 micrograms/ml can increase 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, tumour radiosensitivity and renal function immediately after exposure to appropriate drug concentrations. Using 86Rb extraction, doses of 10-100 mg/kg pentoxifylline were shown to increase relative tumour perfusion 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 perfusion; there was no significant effect in any tissue after 5 mg/kg. Using a clonogenic assay, this increased tumour perfusion was shown to be reflected in increased tumour radiosensitivity to 25 Gy 15 min after pentoxifylline, with the same dose threshold of 10 mg/kg, and similar lack of dose-dependence at higher doses; the response indicated reduction in hypoxic fraction by a factor of 2-3. Renal function, measured by [51Cr]EDTA and [125I]iodohippurate clearance was unaffected at doses up to 50 mg/kg, with a slight effect at 100 mg/kg. The data indicate 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 is effective are compatible with the mechanism being modification of blood cell deformability. Pentoxifylline shows promise as a clinical radiosensitiser acting by direct increase in tumour oxygenation.