Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: Relationship with suppression of circulating TGF-Β1

S. G. Kim, Y. M. Kim, Y. H. Choi, M. G. Lee, J. Y. Choi, J. Y. Han, S. H. Cho, J. W. Jang, S. H. Um, C. Y. Chon, D. H. Lee, J. J. Jang, E. S. Yu, Y. S. Lee

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Abstract

Oltipraz is a potential candidate drug for the treatment of liver fibrosis (LF) and liver cirrhosis (LC). The pharmacokinetics of oltipraz and its major rearranged metabolite (7-methyl-6,8-bis(methylthio)H-pyrrolo1,2-apyrazine (RM)) were evaluated after single-dose (3090mg) and multiple-dose (60mg b.i.d. or 90mg q.d. for 24 weeks) oral administration of oltipraz to patients with LF or LC. Oltipraz was safe and well tolerated in both studies. In the single-dose study, the area under the plasma concentration-time curve (AUC), peak plasma concentration (Cmax), and terminal half-life (t 1/2) of oltipraz as well as the AUC of its RM were dose dependent. Oltipraz was rapidly absorbed; the time to reach Cmax (Tma) was 2-4h. The conversion of oltipraz to RM was also rapid and substantial (AUC of RM from time 0 to the last measured concentration (AUClast, RM)/AUClast, oltipraz, 4261%). In the multiple-dose study, the level of transforming growth factor-Β1 (TGF-Β1) (a blood fibrosis marker) was suppressed at steady-state plasma concentrations of ∼2060ng/ml of oltipraz or of ∼60140ng/ml of oltipraz plus RM. Overall, the pharmacokinetics, safety, and efficacy of oltipraz suggest that it may be helpful in the treatment of patients with LF or LC, at an optimal dosing regimen.

Original languageEnglish
Pages (from-to)360-368
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume88
Issue number3
DOIs
Publication statusPublished - 2010 Sep

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Kim, S. G., Kim, Y. M., Choi, Y. H., Lee, M. G., Choi, J. Y., Han, J. Y., Cho, S. H., Jang, J. W., Um, S. H., Chon, C. Y., Lee, D. H., Jang, J. J., Yu, E. S., & Lee, Y. S. (2010). Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: Relationship with suppression of circulating TGF-Β1. Clinical Pharmacology and Therapeutics, 88(3), 360-368. https://doi.org/10.1038/clpt.2010.89