Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 53, 2023 - Issue 4
160
Views
1
CrossRef citations to date
0
Altmetric
General Xenobiochemistry

Estimation of contribution of CYP2D6 to tipepidine metabolism in humans and prolongation of the half-life of tipepidine by combination use with a CYP2D6 inhibitor in chimeric mice with humanised liver

, , , , &
Pages 241-247 | Received 19 Apr 2023, Accepted 09 Jun 2023, Published online: 15 Jun 2023
 

Abstract

  1. Recently, it has been reported that tipepidine has various central pharmacological effects and can be expected to be safely repositioned as a treatment for psychiatric disorders. Since tipepidine has a very short half-life and requires three doses per day, the development of a once-daily medication would be highly beneficial to improve adherence and quality of life in patients with chronic psychiatric disorders. The aim of this study was to identify the enzymes involved in tipepidine metabolism and to verify that combination use with an enzyme inhibitor prolongs the half-life of tipepidine.

  2. Metabolism studies using recombinant human cytochrome P450 (P450, CYP) isoforms and inhibition studies using various selective P450 inhibitors and human liver microsomes revealed that CYP2D6 is the main enzyme catalysing tipepidine metabolism, with a metabolic contribution ratio of 85.4%.

  3. Furthermore, a pharmacokinetic study using chimeric mice with humanised liver showed that oral coadministration of a CYP2D6 inhibitor, quinidine, increased the Cmax, AUC0-t, and t1/2 of tipepidine by 1.5-, 3.2-, and 3.0-fold, respectively.

  4. These results indicated that coadministration of a CYP2D6 inhibitor is effective in increasing plasma exposure and prolonging the half-life of tipepidine and is useful for repositioning tipepidine as a treatment for psychiatric disorders.

Disclosure statement

The authors declare no conflict of interest. Shun Hayashi, Hiroko Kawaguchi, Takao Watanabe, Izuru Miyawaki are employees of Sumitomo Pharma Co., Ltd.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.