Prediction of circulating human metabolites of pemafibrate, a novel antidyslipidemic drug, using chimeric mice with humanized liver / Shin-ichiro Ogawa, Shotaro Uehara, Yoshihiko Tsunenari, Hiroyuki Kawai, Hiroshi Suemizu, Hiroshi Yamazaki
Abstract Pharmacokinetics and metabolism of recently launched antidyslipidemic drug pemafibrate ((2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) was investigated in chimeric mice with humanized liver in the present study. The plasma unbound fractions of [ 14 C]pemafibrate in mice (0.0046–0.0048) were higher than those in monkeys and humans (0.0015–0.0022). In chimeric mice with humanized liver intravenously treated with pemafibrate at 1.0 mg/kg body weight, the pharmacokinetic parameters (CL total , V ss and AUC 0-inf ) of unbound pemafibrate in chimeric mice with humanized liver were more similar to those reported in monkeys and humans than those in control mice. High concentrations of N -dealkylated form (M4) and benzoxazole 6-hydroxylated form (M6) of pemafibrate in plasma were observed as the main circulating metabolites in chimeric mice with humanized liver treated with pemafibrate. Moreover, the concentrations of other specified metabolites of pemafibrate were much higher in chimeric mice with humanized liver than in control mice. These results suggest that there are species differences in the pharmacokinetics of pemafibrate in vivo between mice tested and humans reported. Moreover, chimeric mice with humanized liver seem to be a beneficial animal model for further studies to predict the circulating human metabolites of pemafibrate and their pharmacokinetics.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:50 |
|---|---|
| Enthalten in: |
Xenobiotica - 50(2020), 7, Seite 769-775 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ogawa, Shin-ichiro [VerfasserIn] |
|---|
| Links: |
FID Access [lizenzpflichtig] |
|---|
| Themen: |
|---|
| Umfang: |
1 Online-Ressource (7 p) |
|---|
| doi: |
10.1080/00498254.2019.1694198 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
KFL011210842 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | KFL011210842 | ||
| 003 | DE-627 | ||
| 005 | 20230720210324.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230714s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/00498254.2019.1694198 |2 doi | |
| 035 | |a (DE-627)KFL011210842 | ||
| 035 | |a (KFL)prod_LgpH_10.1080/00498254.2019.1694198 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 084 | |a PHARM |q DE-84 |2 fid | ||
| 100 | 1 | |a Ogawa, Shin-ichiro |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prediction of circulating human metabolites of pemafibrate, a novel antidyslipidemic drug, using chimeric mice with humanized liver |c Shin-ichiro Ogawa, Shotaro Uehara, Yoshihiko Tsunenari, Hiroyuki Kawai, Hiroshi Suemizu, Hiroshi Yamazaki |
| 264 | 1 | |c 2020 | |
| 300 | |a 1 Online-Ressource (7 p) | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Pharmacokinetics and metabolism of recently launched antidyslipidemic drug pemafibrate ((2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) was investigated in chimeric mice with humanized liver in the present study. The plasma unbound fractions of [ 14 C]pemafibrate in mice (0.0046–0.0048) were higher than those in monkeys and humans (0.0015–0.0022). In chimeric mice with humanized liver intravenously treated with pemafibrate at 1.0 mg/kg body weight, the pharmacokinetic parameters (CL total , V ss and AUC 0-inf ) of unbound pemafibrate in chimeric mice with humanized liver were more similar to those reported in monkeys and humans than those in control mice. High concentrations of N -dealkylated form (M4) and benzoxazole 6-hydroxylated form (M6) of pemafibrate in plasma were observed as the main circulating metabolites in chimeric mice with humanized liver treated with pemafibrate. Moreover, the concentrations of other specified metabolites of pemafibrate were much higher in chimeric mice with humanized liver than in control mice. These results suggest that there are species differences in the pharmacokinetics of pemafibrate in vivo between mice tested and humans reported. Moreover, chimeric mice with humanized liver seem to be a beneficial animal model for further studies to predict the circulating human metabolites of pemafibrate and their pharmacokinetics | ||
| 653 | |a Humanized-liver mice | ||
| 653 | |a species difference | ||
| 653 | |a metabolic pathways | ||
| 700 | 1 | |a Uehara, Shotaro |e verfasserin |4 aut | |
| 700 | 1 | |a Tsunenari, Yoshihiko |e verfasserin |4 aut | |
| 700 | 1 | |a Kawai, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Suemizu, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Yamazaki, Hiroshi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Xenobiotica |d Abingdon : Taylor & Francis Group, 1971 |g 50(2020), 7, Seite 769-775 |h Online-Ressource |w (DE-627)KFL000005959 |w (DE-600)1485113-1 |w (DE-576)079719163 |x 1366-5928 |7 nnns |
| 773 | 1 | 8 | |g volume:50 |g year:2020 |g number:7 |g pages:769-775 |
| 856 | 4 | 0 | |u http://pharmazie.proxy.fid-lizenzen.de/fid/tandf-ejournals-pharmazie/doi.org/10.1080/00498254.2019.1694198 |m X:KFL |x Resolving-System |y FID Access |z lizenzpflichtig |
| 912 | |a ZDB-1-TFE | ||
| 912 | |a GBV_KFL | ||
| 912 | |a FID-PHARM | ||
| 935 | |i IMPORT_0628_prod_LgpH_02 | ||
| 951 | |a AR | ||
| 952 | |d 50 |j 2020 |e 7 |h 769-775 | ||