The importance of villous physiology and morphology in mechanistic physiologically-based pharmacokinetic models.
Pharm Res
; 31(2): 305-21, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-23990312
ABSTRACT
PURPOSE:
Existing PBPK models incorporating intestinal first-pass metabolism account for effect of drug permeability on accessible absorption surface area by use of "effective" permeability, P eff , without adjusting number of enterocytes involved in absorption or proportion of intestinal CYP3A involved in metabolism. The current model expands on existing models by accounting for these factors.METHODS:
The PBPK model was developed using SAAM II. Midazolam clinical data was generated at GlaxoSmithKline.RESULTS:
The model simultaneously captures human midazolam blood concentration profile and previously reported intestinal availability, using values for CYP3A CLu int , permeability and accessible surface area comparable to literature data. Simulations show (1) failure to distinguish absorbing from non-absorbing enterocytes results in overestimation of intestinal metabolism of highly permeable drugs absorbed across the top portion of the villous surface only; (2) first-pass extraction of poorly permeable drugs occurs primarily in enterocytes, drugs with higher permeability are extracted by enterocytes and hepatocytes; (3) CYP3A distribution along crypt-villous axes does not significantly impact intestinal metabolism; (4) differences in permeability of perpetrator and victim drugs results in their spatial separation along the villous axis and intestinal length, diminishing drug-drug interaction magnitude.CONCLUSIONS:
The model provides a useful tool to interrogate intestinal absorption/metabolism of candidate drugs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Midazolam
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Aged
/
Female
/
Humans
/
Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article