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Transporters for Drug Absorption and Distribution

Creative Animodel provides a broad range of services about transporter-mediated drug-drug interactions (DDIs) to evaluate pharmacological and toxicological effects of your drug candidates. With decades of experience in preclinical drug studies, we can help accelerate your projects of drug research and development.

Transporter Mediated DDIs

DDIs refer to the phenomenon whereby the administration of one drug alters the absorption and distribution of another drug. The drug causing the effects can be referred to as the “perpetrator” and the drug that is affected as the “victim”. DDIs can occur through a number of mechanisms, including direct inhibitory mechanisms of the perpetrator at transporters, or induction of proteins that influences the pharmacokinetics of the victim. For example, if the perpetrator inhibits the active transport into the liver of the victim, the initial effects are that the concentration of the victim in the plasma will increase, relative to the concentrations in the absence of the perpetrator. These changes could thus alter the pharmacological and toxicological effects.

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Figure 1. Plasma exposure of a victim drug (transporter substrate) over time in the absence and presence of a perpetrator drug (transporter inhibitor).

Interactions are usually strongly influenced by the relative times of administration and the amount of each drug administered. In general, the closer in time the two drugs are administered the greater the chance of an interaction between them. At one extreme, in cases when interaction is solely due to direct inhibition of transporters, the perpetrator must still be present in the body. In cases involving protein induction or time-varying inhibition mechanisms, it is possible for the interaction effect to be present even after the perpetrator has been cleared from the body.

Classification of Drug Transporters

Transporters are large proteins located in the plasma membrane of cells. They normally span the membrane many times and modulate the transfer of drug substances across cellular membranes, tissues or organ barriers. There are two transporter superfamilies, the ATP-binding cassette (ABC) transporters and the solute carriers (SLCs).

There are seven families of ABC transporter genes (ABCA to ABCG). For drug transport, the ABCB family with MDR1 (also known as P-gp) and BSEP, ABCC family with the MRPs, and ABCG family with BCRP are the most clinically relevant. All mammalian ABC transporters are efflux transporters and transport is driven by ATP hydrolysis. SLCs are classified into 52 different families based on their amino acid identities. Families that have been identified as important for drug transport include SLCO, SLC22 and SLC47. The SLCO family members, including OATP1B1, OATP1B3, SLC22 members OCT1, OCT2, OAT1 and OAT3 for drug uptake, and SLC47 members MATE1 and MATE2-K for drug efflux, are the most relevant in the study of clinical transporter-mediated DDIs, as they transport a number of important therapeutics.

Services at Creative Animodel

• Uptake transporters
> SLCs substrate identification (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2)
> SLCs inhibition (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2)
• Efflux transporters
> BCRP substrate identification
> ABC transporters inhibition (P-gp, BCRP, BSEP)
> SLCs substrate identification (MATE1, MATE2-K)
> SLCs inhibition (MATE1, MATE2-K)
• Permeability
> Tissue permeability
> PAMPA
> Caco-2 Permeability
> MDR1-MDCK permeability
> Wild Type MDCK permeability
• Others
> Single and double transporter knockin/knockout cell-based services
> Other transporter assays available on request

Creative Animodel is a professional contract research organization specialized in providing in vivo and in vitro services for preclinical drug evaluation. We provide one-stop services and customized services to meet your specific needs. If you have any questions, please feel free to contact us. We look forward to establishing cooperation with you in the near future.

Reference:
1. Glynis, N. & Kuresh, Y. Drug Transporters: Role and Importance in ADME and Drug Development. The Royal Society of Chemistry. 2016.

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