Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1984 Sep;50(3):291–303. doi: 10.1038/bjc.1984.176

Preclinical pharmacokinetics of benznidazole.

P Workman, R A White, M I Walton, L N Owen, P R Twentyman
PMCID: PMC1976805  PMID: 6466543

Abstract

Benznidazole is a lipophilic analogue of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU. We have investigated the detailed pharmacokinetics of benznidazole in mice, dogs and sheep to provide a data base for the estimation of doses required for chemosensitization in man. Pharmacokinetic behaviour 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 values were longer than for MISO, being 90 min in mice, 4-5 h in sheep and 9-11 h in dogs. At doses giving linear kinetics, peak whole plasma concentrations per administered mg kg-1 were 0.75 micrograms ml-1 for the i.p. route in mice and 1.8 micrograms 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 tumours and from 14-70% for spontaneous dog neoplasms. Nervous tissue penetration was similar to that in tumours: 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 approximately 5% of the administered dose was excreted unchanged in the urine, indicating the likelihood of extensive metabolism. These data show that 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 micrograms ml-1 and we predict that these will be obtained with oral doses of 6-20 mg kg-1 in man.

Full text

PDF
291

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams G. E., Clarke E. D., Flockhart I. R., Jacobs R. S., Sehmi D. S., Stratford I. J., Wardman P., Watts M. E., Parrick J., Wallace R. G. Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency. Int J Radiat Biol Relat Stud Phys Chem Med. 1979 Feb;35(2):133–150. doi: 10.1080/09553007914550151. [DOI] [PubMed] [Google Scholar]
  2. Anderson R. F., Patel K. B. Effect of lipophilicity of nitroimidazoles on radiosensitization of hypoxic bacterial cells in vitro. Br J Cancer. 1979 Jun;39(6):705–710. doi: 10.1038/bjc.1979.124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown J. M. The mechanisms of cytotoxicity and chemosensitization by misonidazole and other nitroimidazoles. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):675–682. doi: 10.1016/0360-3016(82)90711-8. [DOI] [PubMed] [Google Scholar]
  4. Brown J. M., Workman P. Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole. Radiat Res. 1980 Apr;82(1):171–190. [PubMed] [Google Scholar]
  5. Dische S., Saunders M. I., Lee M. E., Adams G. E., Flockhart I. R. Clinical testing of the radiosensitizer Ro 07-0582: experience with multiple doses. Br J Cancer. 1977 May;35(5):567–579. doi: 10.1038/bjc.1977.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hirst D. G., Brown J. M., Hazlehurst J. L. Effect of partition coefficient on the ability of nitroimidazoles to enhance the cytotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Cancer Res. 1983 May;43(5):1961–1965. [PubMed] [Google Scholar]
  7. Lee F. Y., Workman P. Misonidazole and CCNU: further evidence for a pharmacokinetic mechanism of chemosensitization and therapeutic gain. Br J Cancer. 1984 May;49(5):579–585. doi: 10.1038/bjc.1984.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lee F. Y., Workman P. Modification of CCNU pharmacokinetics by misonidazole--a major mechanism of chemosensitization in mice. Br J Cancer. 1983 May;47(5):659–669. doi: 10.1038/bjc.1983.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. McNally N. J. Enhancement of chemotherapy agents. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):593–598. doi: 10.1016/0360-3016(82)90691-5. [DOI] [PubMed] [Google Scholar]
  10. Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung. 1980;30(12):2192–2194. [PubMed] [Google Scholar]
  11. Raaflaub J., Ziegler W. H. Single-dose pharmacokinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung. 1979;29(10):1611–1614. [PubMed] [Google Scholar]
  12. Sheldon P. W., Batten E. L. Potentiation in vivo of melphalan activity by nitroimidazole compounds. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):635–637. doi: 10.1016/0360-3016(82)90701-5. [DOI] [PubMed] [Google Scholar]
  13. Siemann D. W., Morrissey S., Wolf K. In vivo potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea by the radiation sensitizer benznidazole. Cancer Res. 1983 Mar;43(3):1010–1013. [PubMed] [Google Scholar]
  14. Siemann D. W. Potentiation of chemotherapy by hypoxic cell radiation sensitizers--a review. Int J Radiat Oncol Biol Phys. 1982 Jun;8(6):1029–1034. doi: 10.1016/0360-3016(82)90172-9. [DOI] [PubMed] [Google Scholar]
  15. Twentyman P. R., Bleehen N. M. Studies of "potentially lethal damage" in EMT6 mouse tumour cells treated with bleomycin either in vitro or in vivo. Br J Cancer. 1975 Oct;32(4):491–501. doi: 10.1038/bjc.1975.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Twentyman P. R., Kallman R. F., Brown J. M. The effect of time between X-irradiation and chemotherapy on the growth of three solid mouse tumors--I. Adriamycin. Int J Radiat Oncol Biol Phys. 1979 Aug;5(8):1255–1260. doi: 10.1016/0360-3016(79)90649-7. [DOI] [PubMed] [Google Scholar]
  17. Twentyman P. R., Workman P. Chemosensitization by lipophilic nitroimidazoles. Br J Cancer. 1983 Jul;48(1):17–26. doi: 10.1038/bjc.1983.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. White R. A., Workman P., Brown J. M. 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. Radiat Res. 1980 Dec;84(3):542–561. [PubMed] [Google Scholar]
  19. White R. A., Workman P., Owen L. N., Bleehen N. M. The penetration of misonidazole into spontaneous canine tumours. Br J Cancer. 1979 Aug;40(2):284–294. doi: 10.1038/bjc.1979.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. White R. A., Workman P. Pharmacokinetic and tumour-penetration properties of the hypoxic cell radiosensitizer desmethylmisonidazole (Ro 05-Ro-9963) in dogs. Br J Cancer. 1980 Feb;41(2):268–276. doi: 10.1038/bjc.1980.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. White R., Workman P., Owen L. The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole. Int J Radiat Oncol Biol Phys. 1982 Mar-Apr;8(3-4):473–476. doi: 10.1016/0360-3016(82)90664-2. [DOI] [PubMed] [Google Scholar]
  22. Workman P., Brown J. M. Structure-pharmacokinetic relationships for misonidazole analogues in mice. Cancer Chemother Pharmacol. 1981;6(1):39–49. doi: 10.1007/BF00253009. [DOI] [PubMed] [Google Scholar]
  23. Workman P. Dose-dependence and related studies on the pharmacokinetics of misonidazole and desmethylmisonidazole in mice. Cancer Chemother Pharmacol. 1980;5(1):27–37. doi: 10.1007/BF00578559. [DOI] [PubMed] [Google Scholar]
  24. Workman P., Little C. J., Marten T. R., Dale A. D., Ruane R. J., Flockhart I. R., Bleehen N. M. Estimation of the hypoxic cell-sensitiser misonidazole and its O-demethylated metabolite in biological materials by reversed-phase high-performance liquid chromatography. J Chromatogr. 1978 May 1;145(3):507–512. doi: 10.1016/s0378-4347(00)81386-9. [DOI] [PubMed] [Google Scholar]
  25. Workman P., Twentyman P. R., Lee F. Y., Walton M. I. Drug metabolism and chemosensitization. Nitroimidazoles as inhibitors of drug metabolism. Biochem Pharmacol. 1983 Mar 1;32(5):857–864. doi: 10.1016/0006-2952(83)90588-9. [DOI] [PubMed] [Google Scholar]
  26. Workman P., Twentyman P. R. Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU. Br J Cancer. 1982 Aug;46(2):249–259. doi: 10.1038/bjc.1982.190. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES