Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide.
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ genetics
Animals
Area Under Curve
Gallic Acid
/ administration & dosage
Glucuronides
/ metabolism
Hypolipidemic Agents
/ administration & dosage
Male
Mice
Mice, Knockout
Microsomes, Liver
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
/ genetics
Tissue Distribution
Breast cancer resistance protein
disposition
leonurine
leonurine-10-O-β-glucuronide
liver
multidrug resistance protein 2
Journal
Current drug metabolism
ISSN: 1875-5453
Titre abrégé: Curr Drug Metab
Pays: Netherlands
ID NLM: 100960533
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
07
2020
revised:
21
10
2020
accepted:
03
11
2020
pubmed:
18
11
2020
medline:
21
9
2021
entrez:
17
11
2020
Statut:
ppublish
Résumé
Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) vivo. To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G. The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined. After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05). Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.
Sections du résumé
BACKGROUND
BACKGROUND
Leonurine (Leo), a promising antilipemic agent that has been approved for clinical trials, is extensively metabolized into bioactive Leonurine-10-O-β-glucuronide (L-10-G) vivo.
OBJECTIVE
OBJECTIVE
To explore the effects of breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2) on the disposition of L-10-G.
METHODS
METHODS
The pharmacokinetics, tissue distribution and intestinal perfusion of Leo were studied by using efflux transporter gene knockout mouse models. The enzyme kinetics via liver and intestinal microsomes were also examined.
RESULTS
RESULTS
After intravenous injection with Leo, the AUC0-∞ values of L-10-G in Bcrp1-/- and Mrp2-/- mice were 1.55-fold and 16.80-fold higher, respectively, than those in wild-type FVB mice (P < 0.05). After oral administration, the AUC0-∞ value of L-10-G showed a 2.82-fold increase in Mrp2-/- mice compared with wild-type FVB mice (P < 0.05). After gavage with Leo for 10 and 25 min, the bile accumulation of L-10-G in Mrp2-/- mice was 3-fold and 22-fold lower, respectively, than that in wild-type FVB mice (P < 0.05). Besides, the intestinal excreted amount of L-10-G showed 2.22-fold and 2.68-fold decrease in Bcrp1-/- and Mrp2-/- mice, respectively, compared with that in wild-type FVB mice (P < 0.05). The clearance of L-10-G decreased in liver microsomes and increased in intestinal microsomes of Bcrp1-/- and Mrp2-/- mice compared to the wild-type FVB mice (P < 0.05).
CONCLUSION
CONCLUSIONS
Both Bcrp and Mrp2 are involved in the disposition of L-10-G, and Mrp2 exhibits a superior influence.
Identifiants
pubmed: 33198612
pii: CDM-EPUB-111531
doi: 10.2174/1389200221999201116142742
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Abcg2 protein, mouse
0
Glucuronides
0
Hypolipidemic Agents
0
Multidrug Resistance-Associated Protein 2
0
Multidrug Resistance-Associated Proteins
0
leonurine
09Q5W34QDA
Gallic Acid
632XD903SP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1060-1067Informations de copyright
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.