Preclinical pharmacokinetics of benznidazole

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Abstract
Benznidazole is a lipophilic analog of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea]. The detailed pharmacokinetics of benznidazole was investigated in mice, dogs and sheep to provide a data base for the estimation of doses required for chemosensitization in man. Pharmacokinetic behavior was linear except at high doses in mice. Absorption was fairly rapid and bioavailability was complete following both i.p. administration in mice and oral administration in dogs. Elimination t1/2 [half-life] values were longer than for MISO, being 90 min in mice, 4-5 h in sheep and 9-11 h in dogs. At dose giving linear kinetics, peak whole plasma concentrations per administered mg/kg-1 were 0.75 .mu.g ml-1 for the i.p. route in mice and 1.8 .mu.g ml-1 for the oral route in dogs. Though between 39 and 59% of plasma benznidazole was bound to protein, tissue penetration was generally good. Tissue/whole plasma ratios ranged from 59-99% for transplantable mouse tumors and from 14-70% for spontaneous dog neoplasms. Nervous tissue penetration was similar to that in tumors; brain/whole plasma ratios averaged between 61 and 76% in mice and 42% in dogs, while peripheral nerve/whole plasma ratios in dogs averaged 74%. Mean liver/whole plasma ratios were 42% and 71% in BALB/c and C3H/He mouse strains, respectively. Only .apprx. 5% of the administered dose was excreted unchanged in the urine, indicating the likelihood of extensive metabolism. Benznidazole should have suitable pharmacokinetic properties for clinical use as a chemosensitizer. Enhancement of CCNU response is likely to require circulating benznidazole concentrations of 10-30 .mu.g ml-1. These will probably be otained with oral doses of 6-20 mg kg-1 in man.

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