The Pharmacokinetics and Tumor and Neural Tissue Penetrating Properties of SR-2508 and SR-2555 in the Dog-Hydrophilic Radiosensitizers Potentially Less Toxic than Misonidazole

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Abstract
The behavior of three 2-nitroimidazole drugs of similar electron affinity to misonidazole but with varying octanol:water partition coefficients was compared in normal and tumor-bearing dogs. In particular the pharmacokinetic behavior, urinary excretion and tumor and neural tissue penetrating properties of the 3 drugs [desmethylmisonidazole (Ro 05-9963), SR-2508 and SR-2555] were studied. Peak plasma concentration and plasma clearance rates increased with decreasing lipophilicity by a factor of approximately 3 for the range of partition coefficients (P) studied (0.026-0.43). Urinary excretion of the unchanged drug increased from 6 to 100%; oral bioavailability was considerably impaired by decreasing lipophilicity. Penetration into the CNS and peripheral nervous system was significantly slower for the more polar drugs, due to this and the increased plasma clearance rates, the drug exposure to these sites of potential neurotoxicity was reduced. Peak tumor concentrations increased with decreasing lipophilicity; those for the 2 SR drugs were more than twice those for equimolar i.v. doses of misonidazole. While tumor/plasma ratios were generally unchanged by varying partition coefficient, the duration of peak tumor concentrations was only transient for the more polar drugs. Based on the increased plasma clearance rates, improved peak tumor concentrations and reduced drug exposure to neural tissue, lowering lipophilicity may be an important means of designing radiosensitizing drugs which are less toxic than and superior to misonidazole.