In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms

R. Abbas, C. P. Chow, N. J. Browder, D. Thacker, S. L. Bramer, C. J. Fu, W. Forbes, M. Odomi, D. A. Flockhart

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 μM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 μM) and the CYP2C19 inhibitor omeprazole (10 μM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2 = 0.68, P <0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 μM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

Original languageEnglish (US)
Pages (from-to)178-184
Number of pages7
JournalHuman and Experimental Toxicology
Volume19
Issue number3
StatePublished - 2000
Externally publishedYes

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Metabolism
Cytochrome P-450 Enzyme System
Protein Isoforms
Liver
Hydroxylation
Cytochrome P-450 CYP3A
Hexanes
Liver Microsomes
cilostazol
In Vitro Techniques
Felodipine
Enzyme inhibition
Cytochrome P-450 CYP1A2
Enzyme kinetics
Cytochrome P-450 CYP2D6
Quinidine
Ketoconazole
Omeprazole
Cimetidine
Metabolites

Keywords

  • Cilostazol
  • CYP450
  • In vitro
  • Interaction
  • Isoforms
  • Metabolism

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Abbas, R., Chow, C. P., Browder, N. J., Thacker, D., Bramer, S. L., Fu, C. J., ... Flockhart, D. A. (2000). In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. Human and Experimental Toxicology, 19(3), 178-184.

In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. / Abbas, R.; Chow, C. P.; Browder, N. J.; Thacker, D.; Bramer, S. L.; Fu, C. J.; Forbes, W.; Odomi, M.; Flockhart, D. A.

In: Human and Experimental Toxicology, Vol. 19, No. 3, 2000, p. 178-184.

Research output: Contribution to journalArticle

Abbas, R, Chow, CP, Browder, NJ, Thacker, D, Bramer, SL, Fu, CJ, Forbes, W, Odomi, M & Flockhart, DA 2000, 'In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms', Human and Experimental Toxicology, vol. 19, no. 3, pp. 178-184.
Abbas R, Chow CP, Browder NJ, Thacker D, Bramer SL, Fu CJ et al. In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. Human and Experimental Toxicology. 2000;19(3):178-184.
Abbas, R. ; Chow, C. P. ; Browder, N. J. ; Thacker, D. ; Bramer, S. L. ; Fu, C. J. ; Forbes, W. ; Odomi, M. ; Flockhart, D. A. / In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms. In: Human and Experimental Toxicology. 2000 ; Vol. 19, No. 3. pp. 178-184.
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