Display options
Cite
Bomont HL, Tarbit MH, Humphrey MJ, et al. Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat. Pharm Res. 1994;11(7):951-60doi: 10.1023/a:1018966800208.
Bomont, H. L., Tarbit, M. H., Humphrey, M. J., & Houston, J. B. (1994). Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat. Pharmaceutical research, 11(7), 951-60. https://doi.org/10.1023/a:1018966800208
Bomont, H L, et al. "Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat." Pharmaceutical research vol. 11,7 (1994): 951-60. doi: https://doi.org/10.1023/a:1018966800208
Bomont HL, Tarbit MH, Humphrey MJ, Houston JB. Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat. Pharm Res. 1994 Jul;11(7):951-60. doi: 10.1023/a:1018966800208. PMID: 7937554.
Copy Download .nbib Format: NLM
Share it on

Pharm Res. 1994 Jul;11(7):951-60. doi: 10.1023/a:1018966800208.

Disposition of azole antifungal agents. II. Hepatic binding and clearance of dichlorophenyl-bis-triazolylpropanol (DTP) in the rat.

Pharmaceutical research

H L Bomont, M H Tarbit, M J Humphrey, J B Houston

Affiliations

  1. Department of Pharmacy, University of Manchester, UK.

PMID: 7937554 DOI: 10.1023/a:1018966800208

Abstract

DTP (dichlorophenyl-bis-triazolylpropanol) was evaluated as a probe of drug-cytochromes P450 interactions in vitro and in vivo. Studies with rat liver microsomes demonstrate that DTP shows similar P450 binding affinity to its analog, ketoconazole, as determined by P450 difference spectra and inhibition of the metabolism of methoxycoumarin. As a more polar azole, DTP shows less affinity for rat plasma albumin (fraction unbound 0.56) than ketoconazole (fraction unbound 0.037). DTP metabolism is simpler than that of ketoconazole, with only one pathway, N-dealkylation which removes a triazole ring to yield DTP glycol. This primary metabolite is further metabolised to a carboxylic acid, a glycol glucuronide and a third unknown secondary metabolite (probably an acid glucuronide). Over a dose range of 0.1-24mg/kg there is complete mass balance recovery in urine via the five metabolites and unchanged drug. However DTP metabolism is dose dependent and while the affinity of DTP for the cytochromes P450 carrying out the initial dealkylation is high (1.5 microM based on unbound blood concentration), the capacity of the reaction is low (1 nmole/min). Under linear conditions, metabolic clearance is low (19ml/h), but ten-fold higher than renal clearance. The liver is the major distribution site for both DTP and ketoconazole. At low DTP concentrations, a specific high affinity process dominates the hepatic binding of DTP resulting in a liver:blood partition coefficient of approximately 30. Hepatic binding is concentration dependent and the progressive decrease in partition coefficient observed as the dose of DTP is escalated is coincident with a decrease in volume of distribution. The two saturable processes involved in the disposition of DTP result in an unusual concentration dependency in the blood concentration-time profile of this azole. Following administration of a high dose (10mg/kg) of DTP the log concentration-time profile is sigmoidal. At high concentrations (above 1mg/L) both the N-dealkylation and the hepatic binding of DTP are saturated, but as concentrations fall to approximately 0.05mg/L the former process becomes linear and the time profile is convex over this concentration range. At later times as DTP concentrations decline further, the tissue binding also reaches the linear region and the time profile becomes concave. Only at low concentrations (below 0.05mg/L) do both processes become first order and the true half life is evident.

References

  1. Biochem Pharmacol. 1987 Dec 15;36(24):4277-81 - PubMed
  2. J Pharm Pharmacol. 1980 Jul;32(7):471-7 - PubMed
  3. Drug Metab Dispos. 1984 Sep-Oct;12(5):603-6 - PubMed
  4. Biochem Pharmacol. 1988 Oct 15;37(20):3861-6 - PubMed
  5. Ann N Y Acad Sci. 1971 Jul 6;179:43-66 - PubMed
  6. J Pharmacokinet Biopharm. 1988 Feb;16(1):1-12 - PubMed
  7. Methods Enzymol. 1978;52:372-7 - PubMed
  8. J Pharmacokinet Biopharm. 1974 Oct;2(5):395-415 - PubMed
  9. Gene. 1988 Sep 7;68(2):229-37 - PubMed
  10. Drug Metab Dispos. 1987 Nov-Dec;15(6):735-9 - PubMed
  11. Biochem Pharmacol. 1988 Dec 15;37(24):4643-51 - PubMed
  12. Biochem Pharmacol. 1988 Oct 15;37(20):3975-80 - PubMed
  13. Pharmacol Ther. 1981;15(3):521-52 - PubMed
  14. Pharmacol Rev. 1987 Mar;39(1):1-47 - PubMed
  15. J Pharmacokinet Biopharm. 1979 Feb;7(1):117-25 - PubMed
  16. Mol Pharmacol. 1986 Sep;30(3):287-95 - PubMed
  17. Drug Metab Dispos. 1985 Mar-Apr;13(2):156-62 - PubMed
  18. Br J Exp Pathol. 1985 Dec;66(6):737-42 - PubMed
  19. Pharm Res. 1988 Feb;5(2):67-75 - PubMed
  20. Pharm Res. 1993 Mar;10(3):418-22 - PubMed
  21. J Pharm Sci. 1989 Jul;78(7):541-6 - PubMed
  22. J Pharm Sci. 1979 Sep;68(9):1203-5 - PubMed
  23. Xenobiotica. 1987 Jan;17(1):45-57 - PubMed
  24. Biochem Pharmacol. 1987 Jan 15;36(2):229-35 - PubMed
  25. Biochem Pharmacol. 1988 Feb 1;37(3):401-8 - PubMed

Substances

MeSH terms

Publication Types