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Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance01:07

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Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
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Drug disposition in pathophysiological conditions.

Adarsh Gandhi1, Bhagavatula Moorthy, Romi Ghose

  • 1Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77030, USA.

Current Drug Metabolism
|July 4, 2012
PubMed
Summary
This summary is machine-generated.

Drug metabolism and disposition are altered in diseases, impacting medication safety and efficacy. Understanding these changes in drug metabolizing enzymes (DMEs) and transporters is crucial for personalized pharmacotherapy.

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Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Pathophysiology

Background:

  • Drug metabolizing enzymes (DMEs) and transporters influence drug efficacy and safety.
  • Pathophysiological conditions like inflammation, cancer, and diabetes alter DME and transporter activity.
  • Altered drug disposition can lead to reduced therapeutic effects or increased toxicity, especially for narrow therapeutic index drugs.

Purpose of the Study:

  • To review how drug disposition is altered in various pathophysiological conditions.
  • To discuss the implications of altered drug metabolizing enzymes and transporters on pharmacotherapy.
  • To explore the role of inflammation and cell signaling in regulating drug metabolism.

Main Methods:

  • Literature review of studies on drug disposition in disease states.
  • Analysis of mechanisms underlying altered expression and activity of DMEs and transporters.
  • Discussion of the impact on pharmacokinetics and pharmacodynamics.

Main Results:

  • Disease states significantly alter drug metabolism and disposition by affecting DMEs and transporters.
  • Inflammation, via cytokines and TLRs, down-regulates DMEs and transporters.
  • Altered drug disposition contributes to inter-individual variability in drug response.

Conclusions:

  • Understanding altered drug disposition in disease is vital for optimizing pharmacotherapy.
  • Mechanistic insights into DME and transporter regulation in disease can guide drug design.
  • Future tools for predicting drug response and improving drug development are facilitated by this knowledge.