Metabolic profiles of coumarin in human plasma extrapolated from a rat data set with a simplified physiologically based pharmacokinetic model
-
- Miura Tomonori
- Showa Pharmaceutical University
-
- Kamiya Yusuke
- Showa Pharmaceutical University
-
- Hina Shiori
- Showa Pharmaceutical University
-
- Kobayashi Yui
- Showa Pharmaceutical University
-
- Murayama Norie
- Showa Pharmaceutical University
-
- Shimizu Makiko
- Showa Pharmaceutical University
-
- Yamazaki Hiroshi
- Showa Pharmaceutical University
Search this article
Abstract
<p>Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro–in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.</p>
Journal
-
- The Journal of Toxicological Sciences
-
The Journal of Toxicological Sciences 45 (11), 695-700, 2020
The Japanese Society of Toxicology
- Tweet
Details 詳細情報について
-
- CRID
- 1390004951539069184
-
- NII Article ID
- 130007935150
-
- NII Book ID
- AN00002808
-
- ISSN
- 18803989
- 03881350
-
- NDL BIB ID
- 031220644
-
- PubMed
- 33132243
-
- Text Lang
- en
-
- Data Source
-
- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
-
- Abstract License Flag
- Disallowed