DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on December 1, 2008; DOI: 10.1124/dmd.108.021949

0090-9556/09/3703-608-618$20.00
DMD 37:608-618, 2009

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.108.021949v1
37/3/608    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Haddish-Berhane, N.
Right arrow Articles by Keshavarzian, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haddish-Berhane, N.
Right arrow Articles by Keshavarzian, A.

SIMDOT-AbMe: Microphysiologically Based Simulation Tool for Quantitative Prediction of Systemic and Local Bioavailability of Targeted Oral Delivery Formulations

Nahor Haddish-Berhane, Ashkan Farhadi, Chell Nyquist, Kamyar Haghighi, and Ali Keshavarzian

Pfizer Inc., Groton, Connecticut (N.H.-B.); Department of Gastroenterology and Nutrition, Rush University Medical Center, Chicago, Illinois (A.F., A.K.); and Agricultural and Biological Engineering (K.H.) and Engineering Education (C.N.), Purdue University, West Lafayette, Indiana

The purpose of this study was to develop a physiologically based simulation tool that is able to predict local as well as systemic bioavailability of 5-aminosalicylic acid (5-ASA)-targeted delivery formulations using the existing understanding of the transport and metabolism mechanisms of 5-ASA. The model accounts for active and passive transcellular transport (absorptive and efflux), passive paracellular transport, intestinal biotransformation, and systemic metabolism and clearance. The intestinal physiology was represented by transverse segments for ileum and proximal colon and longitudinal compartments for the microphysiology of the intestinal tissue. The tool, equipped with an optimization routine that enables tuning model parameters, was developed in Matlab and uses a user-friendly graphical interface for data input and output. Physiologic and kinetic model parameters were estimated either from literature monolayer transport studies using nonlinear curve fitting or obtained directly from the literature. 5-ASA clinical pharmacokinetic profiles of a once-daily (one 4-g/day dose) and twice-daily (two 2-g/day doses) dosing regimen were used to partially calibrate and validate the model, respectively. Simulation results showed that drug Cmax in the gut mucosal layers reached a higher level and was achieved sooner than in the systemic blood level. The computed relative local bioavailability with respect to the systemic bioavailability was 0.063. With use of the model, the relative local bioavailability of different formulations can be established for fast performance verification of new preparations based on measured systemic bioavailability. These types of models play a critical role in designing such preparations and rapidly assessing their effectiveness and will foster efficient experimental designs, saving time and resources.

Address correspondence to: Dr. Nahor Haddish-Berhane, Eastern Point Road, Groton, CT 06340. E-mail: nahor.haddish-berhane{at}pfizercom






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2009 by the American Society for Pharmacology and Experimental Therapeutics.