The importance of drug transporter characterization to precision medicine

Fisel, Pascale; Nies, Anne T.; Schaeffeler, Elke; Schwab, Matthias

doi:10.1080/17425255.2017.1290083

Cited by 11 publications

(7 citation statements)

References 15 publications

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“…The expression and function of transport proteins is not only affected by genetic variation, but also by nongenetic factors, such as age, gender, or disease state, regulatory factors, like transcription factors, or by epigenetic mechanisms. 80 Regarding regulation of MCT expression, again, mainly MCT1, MCT2, and MCT4 were examined. The regulation of MCT gene expression has to be tissue-specific and, if necessary, very rapid in order to enable adaption to changes in activity or different metabolic states.…”

Section: Epigenetic Regulation Of Mct Family Membersmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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The solute carrier (SLC) SLC16 gene family comprises 14 members and encodes for monocarboxylate transporters (MCTs), which mediate the absorption and distribution of monocarboxylic compounds across plasma membranes. As the knowledge about their physiological function, activity, and regulation increases, their involvement and contribution to cancer and other diseases become increasingly evident. Moreover, promising opportunities for therapeutic interventions by directly targeting their endogenous functions or by exploiting their ability to deliver drugs to specific organ sites emerge.

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Section: Epigenetic Regulation Of Mct Family Membersmentioning

confidence: 99%

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

Fisel

Schaeffeler

Schwab

2018

Clinical Translational Sci

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“…As mentioned, SLC and ABC transporters play a key role in the absorption, distribution and elimination of xenobiotics. Interindividual variability of these transporters can lead to differences in therapy and even adverse drug reactions (46,47). This phenomenon may be due to several factors or a combination of factors.…”

Section: Interindividual Variabilitymentioning

confidence: 99%

“…This phenomenon may be due to several factors or a combination of factors. Among them are: non-genetic factors, including age, sex, ethnicity, kidney diseases or medication; genetic variations; and epigenetic mechanisms, such as DNA methylation, histone modifications, or miRNAs (46,48,49).…”

Section: Interindividual Variabilitymentioning

confidence: 99%

“…Genetic polymorphisms, more specifically single nucleotide polymorphisms (SNPs) in the URAT1 gene, cause renal hyperuricemia and hypouricemia (18,23). SLC22A1, a gene encoding OCT1, is highly polymorphic and its expression and function is commonly influenced by several factors (46). Genetic variations in the formation of OCT also cause changes in the intracellular concentrations of metformin and cisplatin, for example (9,20).…”

Section: Interindividual Variabilitymentioning

confidence: 99%

“…The mechanisms of epigenetic regulation are processes that alter transcription without altering the DNA sequence. Figure 6 presents some examples of epigenetic changes (23,42,46). Figure 6.…”

Section: Interindividual Variabilitymentioning

confidence: 99%

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Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level

2020

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Transporters are large membrane proteins, which control the passage of various compounds through biological membranes. These proteins are divided into uptake and efflux transporters and play an important role in the toxicokinetics of many endobiotics and xenobiotics. The uptake transporters facilitate the absorption of these compounds from the blood into the proximal tubular cells, while the efflux transporters eliminate these compounds into tubular fluid (urine). Overall, the uptake is performed by the superfamily solute carrier (SLC) transporters, which are, mostly, located in the basolateral membrane. The organic anion transporters (OATs; SLC22), the organic cation transporters (OCTs; SLC22), the organic cation/carnitine transporters (OCTNs), and the organic anion transporting polypeptides (OATP; SLC21/SLCO) are some examples of uptake transporters of the SLC superfamily. On the other hand, the superfamily ATP-binding cassette (ABC) transporters carry out the elimination of the substances through the apical membrane of the proximal tubular cells. The multidrug resistance proteins 1 (MDR; ABCB), the multi resistance protein (MRP2; ABCC) and the breast cancer resistance protein (BCRP, ABCG) along with the multidrug and toxin extrusion (MATE), which is an SLC transporter, carry out the substance efflux of the cell, However, uptake transporters seem to be more efficient than efflux transporters, leading to an accumulation of compounds in proximal tubular cells and, consequently, to renal damage. The accumulation of compounds can also occur due to variations in the number of transporters that exist due to differences in sex, age, genetic polymorphisms and epigenetics. Furthermore, some substances can inhibit, induce or, eventually, activate these transporters, with consequent drug-drug interactions (DDIs) as a result of alterations on the toxicokinetics of xenobiotics, leading to an increase of their accumulation and, consequently, to renal damage. These compounds may be exogenous, such as antibiotics, antivirals, cisplatin, metals, herbicides, mycotoxins and drugs; or endogenous, like uric acid, bile acids, bilirubin conjugates and conjugated steroids. Thus, in this review, we will focus on the accumulation of exogenous compounds due to variations on renal transporters and the consequent biological effects caused by them.

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