Drug transporters: gatekeepers controlling access of xenobiotics to the cellular interior

Area of Science:

• Pharmacology and Toxicology
• Drug Metabolism and Pharmacokinetics (DMPK)
• Animal Models in Drug Research

Background:

• Drug transporters significantly influence xenobiotic distribution and bioavailability.
• Null mouse models (e.g., P-glycoprotein and MRP null mice) are established tools for studying transporter roles.
• These conventional models have limitations in assessing the specific activity of deleted transporters.

Purpose of the Study:

• To evaluate existing methodologies and null mouse models for studying drug transporter function.
• To highlight the advantages and limitations of conventional null mouse models.
• To introduce humanized mouse models as an advanced approach for transporter research.

Main Methods:

• Review and evaluation of in vitro and in vivo methodologies for drug transporter studies.
• Analysis of P-glycoprotein and MRP null mouse models for xenobiotic distribution assessment.
• Exploration of humanized mouse models to study the functional consequences of transporter replacement.

Main Results:

• Null mouse models effectively exclude specific transporters but cannot study their activity.
• Humanized mice enable a stepwise investigation from wild-type to human transporter function.
• This progression allows for a detailed understanding of species-specific transporter effects.

Conclusions:

• Humanized mouse models represent a logical advancement over conventional null models for drug transporter research.
• These models facilitate a deeper understanding of drug disposition and bioavailability influenced by human transporters.
• The methodologies discussed are essential for accurate preclinical drug development and safety assessment.