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Efflux Cell Membrane Transporters involved in Drug Transport and Drug Interactions

Summary:

  • Transporters are cell membrane proteins involved in the movement of nutrients, wastes, toxins and xenobiotics in and out the cell.
  • Medications not only depend on some of these transporters for their metabolism, elimination and therapeutic efficacy, but may also inhibit or induce transporters, thereby potentially changing the concentrations of other medications that are influenced by these transporters.
  • The genes that make efflux transporters most commonly come from the ATP binding cassette (ABC) superfamily, whereas the genes for influx transporters most commonly come from the solute-linked carrier (SLC) superfamily.
  • Influx and efflux transporters are most commonly found in the brain, gastrointestinal tract, liver, and kidneys.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: October 2015

Explanation

  • As a review, many drug interactions that are not easily explained by an effect on the cytochrome P450 (CYP) enzyme system can now be explained by their influence on influx and efflux cell membrane transporters.1-4  Often times these cell membrane transporters work in conjunction with drug metabolizing enzymes, such as the CYP enzyme system, for overall drug elimination. 

    Efflux cell membrane transporters are not only responsible for moving the parent drug and metabolites of some medications out of the cell, but may also contribute to drug resistance by diminishing the desired therapeutic or biologic effect.2  As such, anything that prevents or inhibits a medication from being transported out of certain cells could result in excessive blood concentrations of the medication and cause undesired side effects.  Moreover, an up-regulation of the number of efflux cell membrane transporters can result in the increased removal of medication, thereby resulting in an increased risk for therapeutic failure.  In addition to inhibition or induction of CYP enzymes involved in drug metabolism, a number of medications can also inhibit or induce efflux cell membrane transporters.  Therefore, clinicians need to become aware of the role and degree of influence that each of these systems have when investigating drug interactions.

    The most common transporters identified to date can be broken down into two main types (or super families), those that are ATP binding cassette (ABC) and those that are solute linked carriers/transporters (SLC).  ABC transporters are primary active transporters that use ATP hydrolysis to move substrates across the cell membrane; whereas, SLC transporters are facilitated or ion-coupled secondary active transporters.5,6  The genes that encode each type of transporter is partially identified by the superfamily it comes from.  For example, there are at least 49 genes for the various ABC transporters.2,5  For SLC transporters, there are known to be at least 43 families representing approximately 300 different transporters.  Therefore, each transporter will have its own gene name (see table).2  In addition, each gene may rely on a different transcription factor to turn on gene transcription for production of more transporters.  Recognizing that medications may alter gene transcription by influencing transcription factors will enable clinicians to identify medications that can inhibit or induce the activity of a transporter.  Just as medications can directly influence active CYP enzymes or influence their production to cause a change in another medication's concentration so can medications influence transporter function.1-4  To complicate things further, some medications affect both metabolic enzymes as well as transporters.  In regard to efflux transporters, most are from the ABC superfamily while influx transporters are more commonly from the SLC superfamily.  Regardless of the type of transporter, they are both generally located in the brain, gastrointestinal tract, liver and kidney. 

    Recognizing the influence of efflux transporters on the movement of certain medications throughout the body is important for understanding a medication's efficacy, metabolism, elimination and potential for causing or being implicated in drug interactions. This database has several clinically relevant examples of drug interactions that are highly influenced by cell membrane transporters.

    References:

    1. United States Food and Drug Administration.  Guidance for Industry.  Drug Interaction Studies - Study Design, Data Analysis, and Implications for Dosing and Labeling.  September 2006. Clinical Pharmacology. Accessed last on 5/19/2009.
    2. Giacomini KM, Sugiyama Y.  Membrane transporters and drug response.  In: Goodman & Gilman's The Pharmacologic Basis of Therapeutics.  11thed. Brunton LL, Lazo JS, Parker KL eds.  McGraw-Hill Medical Publishing Division.  New York, NY. 2006;41-70.
    3. Kim RB.  Transporters and xenobiotic disposition.  Toxicology 2002;181-182:291-7.
    4. Dresser MJ, Leabman MK, Giamcomini KM.  Transporters involved in the elimination of drug in the kidney: organic anion transporters and organic cation transporters.  J Pharm Sci  2001;90:397-421.
    5. Borst P, Elferink RO.  Mammalian ABC transporters in health and disease.  Annu Rev Biochem  2002;71:537-92.
    6. Hediger MA, Coady MJ, Ikeda TS et al.  Expression cloning and cDNA sequencing of the Na+/glucose co-transporter.  Nature 1987;330:379-81.

MESH Terms & Keywords

  • Efflux Transporter, Drug Transporters, BCRP, BSEP, MDR, P-gp, Pgp, MRP