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In vitro inhibition of CYP2C9-mediated warfarin 7-hydroxylation by iguratimod: possible mechanism of iguratimod-warfarin interaction.
Biol Pharm Bull. 2015; 38(3):441-7.BP

Abstract

Iguratimod is a novel disease-modifying antirheumatic drug. A blue letter (safety advisory) for drug interaction between iguratimod and warfarin was issued by the Ministry of Health, Labour and Welfare of Japan in May 2013. Iguratimod may affect warfarin metabolism catalyzed by CYP. However, it is not clear whether iguratimod inhibits warfarin oxidation. This study was performed to investigate the effects of iguratimod on warfarin 7-hydroxylation with human liver microsomes (HLMs) and recombinant CYP enzymes. Iguratimod concentration-dependently inhibited R,S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 15.2 µM. The inhibitory effect was examined with S-warfarin and R-warfarin to determine which enantiomer was more potently inhibited by iguratimod. Iguratimod potently inhibited the S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 14.1 µM, but showed only slight inhibition of R-warfarin 7-hydroxylation. Furthermore, iguratimod inhibited the S-warfarin 7-hydroxylase activity of recombinant CYP2C9.1 (rCYP2C9.1) and rCYP2C9.3 in a concentration-dependent manner with IC50 values of 10.8 and 20.1 µM, respectively. Kinetic analysis of the inhibition of S-warfarin 7-hydroxylation by iguratimod indicated competitive-type inhibition for HLMs and rCYP2C9.1 but mixed-type inhibition for rCYP2C9.3. The Ki values for HLMs, rCYP2C9.1, and rCYP2C9.3 were 6.74, 4.23, and 14.2 µM, respectively. Iguratimod did not exert metabolism-dependent inhibition of S-warfarin 7-hydroxylation. These results indicated that iguratimod is a potent direct inhibitor of CYP2C9-mediated warfarin 7-hydroxylation and that its inhibitory effect on CYP2C9.1 was more sensitive than that on CYP2C9.3.

Authors+Show Affiliations

Department of Pharmacy, Shinshu University Hospital, 3-1-1;Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University 390-8621, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25757926

Citation

Yamaori, Satoshi, et al. "In Vitro Inhibition of CYP2C9-mediated Warfarin 7-hydroxylation By Iguratimod: Possible Mechanism of Iguratimod-warfarin Interaction." Biological & Pharmaceutical Bulletin, vol. 38, no. 3, 2015, pp. 441-7.
Yamaori S, Takami K, Shiozawa A, et al. In vitro inhibition of CYP2C9-mediated warfarin 7-hydroxylation by iguratimod: possible mechanism of iguratimod-warfarin interaction. Biol Pharm Bull. 2015;38(3):441-7.
Yamaori, S., Takami, K., Shiozawa, A., Sakuyama, K., Matsuzawa, N., & Ohmori, S. (2015). In vitro inhibition of CYP2C9-mediated warfarin 7-hydroxylation by iguratimod: possible mechanism of iguratimod-warfarin interaction. Biological & Pharmaceutical Bulletin, 38(3), 441-7. https://doi.org/10.1248/bpb.b14-00711
Yamaori S, et al. In Vitro Inhibition of CYP2C9-mediated Warfarin 7-hydroxylation By Iguratimod: Possible Mechanism of Iguratimod-warfarin Interaction. Biol Pharm Bull. 2015;38(3):441-7. PubMed PMID: 25757926.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro inhibition of CYP2C9-mediated warfarin 7-hydroxylation by iguratimod: possible mechanism of iguratimod-warfarin interaction. AU - Yamaori,Satoshi, AU - Takami,Ken, AU - Shiozawa,Ayaka, AU - Sakuyama,Kanako, AU - Matsuzawa,Naoki, AU - Ohmori,Shigeru, Y1 - 2015/01/19/ PY - 2015/3/12/entrez PY - 2015/3/12/pubmed PY - 2015/12/15/medline SP - 441 EP - 7 JF - Biological & pharmaceutical bulletin JO - Biol. Pharm. Bull. VL - 38 IS - 3 N2 - Iguratimod is a novel disease-modifying antirheumatic drug. A blue letter (safety advisory) for drug interaction between iguratimod and warfarin was issued by the Ministry of Health, Labour and Welfare of Japan in May 2013. Iguratimod may affect warfarin metabolism catalyzed by CYP. However, it is not clear whether iguratimod inhibits warfarin oxidation. This study was performed to investigate the effects of iguratimod on warfarin 7-hydroxylation with human liver microsomes (HLMs) and recombinant CYP enzymes. Iguratimod concentration-dependently inhibited R,S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 15.2 µM. The inhibitory effect was examined with S-warfarin and R-warfarin to determine which enantiomer was more potently inhibited by iguratimod. Iguratimod potently inhibited the S-warfarin 7-hydroxylase activity of HLMs with an IC50 value of 14.1 µM, but showed only slight inhibition of R-warfarin 7-hydroxylation. Furthermore, iguratimod inhibited the S-warfarin 7-hydroxylase activity of recombinant CYP2C9.1 (rCYP2C9.1) and rCYP2C9.3 in a concentration-dependent manner with IC50 values of 10.8 and 20.1 µM, respectively. Kinetic analysis of the inhibition of S-warfarin 7-hydroxylation by iguratimod indicated competitive-type inhibition for HLMs and rCYP2C9.1 but mixed-type inhibition for rCYP2C9.3. The Ki values for HLMs, rCYP2C9.1, and rCYP2C9.3 were 6.74, 4.23, and 14.2 µM, respectively. Iguratimod did not exert metabolism-dependent inhibition of S-warfarin 7-hydroxylation. These results indicated that iguratimod is a potent direct inhibitor of CYP2C9-mediated warfarin 7-hydroxylation and that its inhibitory effect on CYP2C9.1 was more sensitive than that on CYP2C9.3. SN - 1347-5215 UR - https://www.unboundmedicine.com/medline/citation/25757926/In_vitro_inhibition_of_CYP2C9_mediated_warfarin_7_hydroxylation_by_iguratimod:_possible_mechanism_of_iguratimod_warfarin_interaction_ L2 - https://dx.doi.org/10.1248/bpb.b14-00711 DB - PRIME DP - Unbound Medicine ER -