the past decade, transporters of medications have emerged as an important new
area that is paramount to understanding drug interactions. In fact, 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.1,2,3,4 Often times these cell membrane
transporters work in conjunction with drug metabolizing enzymes, such as the
CYP enzyme system, for drug elimination.
cell membrane transporters are not only responsible for bringing in needed
nutrients into the cell, but are also necessary for movement of medications
intracellularly where they will be brought into contact with enzymes
responsible for their metabolism and preparation for elimination or possibly to
exert their therapeutic or biologic effect.2 As such, anything that
prevents or inhibits a medication from getting inside the target cells for
metabolism or to exert its therapeutic effects could result in excessive blood
concentrations of the medication and cause undesired side effects. In
addition to inhibition or induction of CYP enzymes involved in drug metabolism,
a number of medications can also inhibit or induce influx cell membrane
transporters. Therefore, clinicians need to become aware of the role and
degree of influence that each of these systems has when investigating drug
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 influx transporters, most are from the
SLC superfamily while efflux transporters are more commonly from the ABC
superfamily. Regardless of the type of transporter, they are both
generally located in the brain, gastrointestinal tract, liver and kidney.
the influence of influx 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
- 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.
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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.
- Kim RB. Transporters and xenobiotic disposition. Toxicology 2002;181-182:291-7.
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.
- Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem 2002;71:537-92.
MA, Coady MJ, Ikeda TS et al. Expression cloning and cDNA sequencing
of the Na+/glucose co-transporter. Nature 1987;330:379-81.