Age-and Region-Dependent Disposition of Raloxifene in Rats.
PK
Raloxifene
age
glucuronidation
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
27
04
2021
accepted:
15
07
2021
pubmed:
30
7
2021
medline:
18
1
2022
entrez:
29
7
2021
Statut:
ppublish
Résumé
Raloxifene undergoes extensive glucuronidation in the gastrointestinal (GI) tract and the liver. However, the impact of age on raloxifene disposition has never been studied. The purpose of this paper is to determine glucuronidation and Pharmacokinetics (PK) profiles of raloxifene in rats at different ages. Raloxifene glucuronidation was characterized using S9 fractions prepared from different intestinal segments and the liver of F344 rats at 4-, 11-, and 28-week. PK studies were conducted to determine raloxifene oral bioavailability at different ages. Raloxifene and its glucuronides were quantified using LC-MS/MS. Raloxifene-6-glucuronide and raloxifene-4'-glucuronide were detected as the major metabolites and the ratio of these two glucuronides were different ranging from 2.1 to 4.9 folds in the ileum, jejunum, liver, and duodenum, and from 14.5 to 50 folds in the colon. The clearances in the duodenum at 4-week for both two glucuronides were significantly lower than those at the other two ages. PK studies showed that the oral bioavailability of raloxifene is age dependent. The absolute oral bioavailability of raloxifene was 3.5-folds higher at 4-week compared to that at 11-weeks. When raloxifene was administered through IV bolus, its half-life was 5.9 ± 1.16 h and 3.7 ± 0.68 h at 11-and 4-week, respectively. These findings suggested that raloxifene metabolism in the duodenum was significantly slower at young age in rats, which increased the oral bioavailability of raloxifene. At 11-week, enterohepatic recycling efficiency was higher than that of 4-week. Raloxifene's dose at different ages should be carefully considered.
Identifiants
pubmed: 34322833
doi: 10.1007/s11095-021-03084-y
pii: 10.1007/s11095-021-03084-y
pmc: PMC8452384
mid: NIHMS1735774
doi:
Substances chimiques
Glucuronates
0
Piperidines
0
Ugt1a1 protein, rat
0
raloxifene-4'-beta-glucuronide
0
raloxifene-6-beta-glucuronide
0
Raloxifene Hydrochloride
4F86W47BR6
Glucuronosyltransferase
EC 2.4.1.17
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1357-1367Subventions
Organisme : Cancer Prevention and Research Institute of Texas
ID : RP190672
Organisme : NIGMS NIH HHS
ID : R15 GM126475
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007605
Pays : United States
Organisme : NIMHD NIH HHS
ID : U24 MD015970
Pays : United States
Organisme : NIGMS NIH HHS
ID : 1R15GM126475-01A1
Pays : United States
Organisme : Cancer Prevention and Research Institute of Texas
ID : RP180748
Organisme : national center on minority health and health disparities
ID : U54MD007605
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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