Quantitative prediction of human intestinal glucuronidation effects on intestinal availability of UDP-glucuronosyltransferase substrates using in vitro data.
Drug Metab Dispos
; 40(9): 1771-7, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22685216
ABSTRACT
We investigated whether the effects of intestinal glucuronidation on the first-pass effect can be predicted from in vitro data for UDP-glucuronosyltransferase (UGT) substrates. Human in vitro intrinsic glucuronidation clearance (CL(int, UGT)) for 11 UGT substrates was evaluated using pooled intestinal microsomes (4.00-4620 µl · min⻹ · mg⻹) and corrected by the free fraction in the microsomal mixture (CLu(int), (UGT) = 5.2-5133 µl · min⻹ · mg⻹). Eleven UGT substrates were stable against intestinal cytochrome P450, indicating intestinal glucuronidation has a main effect on human intestinal availability. Oral absorbability intestinal availability (F(a)F(g)) values were calculated from in vivo pharmacokinetic parameters in the literature (F(a)F(g) = 0.01-1.0). It was found that CLu(int, UGT) and human F(a)F(g) have an inverse relationship that can be fitted to a simplified intestinal availability model. Experiments using Supersomes from insect cells expressing UGT isoforms showed that the substrates used were conjugated by various UGT isoforms. These results suggest that combining the simplified intestinal availability model and in vitro conjugation assay make it possible to predict human F(a)F(g) regardless of UGT isoform.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Preparações Farmacêuticas
/
Glucuronosiltransferase
/
Glucuronídeos
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Intestinos
/
Modelos Biológicos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article