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Models and Methods to Evaluate Transport of Drug Delivery Systems Across Cellular Barriers
Published on: October 17, 2013
Targeting intestinal transporters for optimizing oral drug absorption
Manthena V Varma1, Catherine M Ambler, Mohammad Ullah
1Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Eastern Point Road, Groton, CT 06340, USA.
Current Drug Metabolism
|December 30, 2010
Summary
Targeting intestinal transporters can optimize oral drug absorption for hydrophilic compounds. This review explores how influx and efflux transporters influence drug delivery and discusses strategies for enhancing oral bioavailability.
Area of Science:
- Pharmacology
- Drug Discovery
- Biopharmaceutics
Background:
- Modern drug discovery trends favor hydrophilic compounds, posing challenges for oral absorption due to membrane permeability.
- Intestinal transporters significantly influence oral drug absorption, with influx transporters facilitating and efflux pumps limiting it.
Purpose of the Study:
- To review intestinal transporters for optimizing oral plasma exposure of hydrophilic and polar drugs.
- To discuss the structure, mechanism, structure-activity relationships, and clinical roles of these transporters.
Main Methods:
- Literature review focusing on intestinal influx and efflux transporters.
- Analysis of physicochemical properties, structure-activity relationships, and pharmacophore modeling.
- Discussion of challenges in transporter research and clinical translation.
Main Results:
- Physicochemical properties like lipophilicity correlate with efflux pump activity.
- Lack of crystal structures and limited substrate data hinder definitive property identification for transporter affinity.
- Gaps exist in translating in vitro findings to clinical relevance.
Conclusions:
- Targeting intestinal transporters is crucial for drugs with high solubility/low passive permeability (BCS Class III/IV).
- Consideration of transporter clearance (Vmax/Km) is essential when targeting specific transporters.
- High-capacity uptake transporters (e.g., PepT1, MCT1) are suitable for high oral dose drugs.
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