Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

König, Jörg; Müller, Fabian; Fromm, Martin F.

doi:10.1124/pr.113.007518

Cited by 501 publications

(395 citation statements)

References 302 publications

(286 reference statements)

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“…Among others, the targets included several membrane transporters known to be involved in metformin pharmacokinetics including solute carrier family 22 members SLC22A1/OCT1 and SLC22A/OCT2, the main transporters for metformin uptake and clearance, respectively, and multidrug and toxin extrusion protein MATE1/SLC47A1, which mediates metformin secretion (Pernicova & Korbonits, 2014). Other transporters included several members of the uptake organic anion transporting polypeptides (OATP) family (SLC21/SLCO) such as SLCO1B1/OATP1B1, SLCO2B1/OATP2B1, and SLCO1B3/OATP1B3, which are known to transport statins, antibiotics, chemotherapeutics, antihistaminic drugs, and diuretics (König, Müller & Fromm, 2013). In addition, the intracellular proton‐assisted amino acid transporter 1 PAT1/SLC36A1, which is an essential component of the amino acid‐sensing engine that drives mTORC1 activation from late endosomes and lysosomes, was included (Heublein et al., 2010).…”

Section: Resultsmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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Section: Resultsmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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“…Furthermore, drug efflux transporters that are localized to the brush border membrane, such as MRP2, which mediates efflux of PIs and NRTIs, and BCRP, which is capable of transporting many NRTIs and rilpivirine, were also downregulated in HIV-infected ARV-naive subjects (16). Given the localization of MRP2 and BCRP at the apical brush border membrane of enterocytes, downregulation in their protein expression is likely to lead to increased drug accumulation within enterocytes and increased drug permeability across the intestinal epithelium in the absorptive direction (33). These findings are in agreement with previously reported downregulation of drug efflux transporters in the sigmoid colon epithelia of ARTnaive HIV-infected men, who had significantly lower Pgp and MRP2 protein expression than healthy individuals (27).…”

Section: Discussionmentioning

confidence: 99%

“…study demonstrating 1.9-and 1.5-fold-higher Pgp and MRP2 protein expression, respectively, in the sigmoid colon biopsy specimens from HIV ϩ subjects receiving ART than in the HIV ϩ treatment-naive group and/or the control group (27). Pgp is expressed at the apical membrane of enterocytes, where it mediates active efflux of drug substrates, including all PIs, some NRTIs (e.g., abacavir and tenofovir disoproxil fumarate [TDF]), and other ARVs (e.g., raltegravir, elvitegravir, and maraviroc) back into the intestinal lumen (16,33). Hence, increased Pgp expression can lead to increased clearance of these ARVs from intestinal tissue in ARTtreated HIV ϩ patients and will likely decrease their intracellular accumulation in enterocytes and permeativity across the intestinal epithelium.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis

Sankaran-Walters

Hoque

et al. 2016

Antimicrob Agents Chemother

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؉ ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2/MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2/BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV ؉ naive group than in the control group and was partially restored to baseline levels in HIV ؉ subjects receiving ART. In contrast, gene and protein expression of ABCB1/Pgp was significantly increased in HIV ؉ subjects on ART relative to HIV ؉ ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV ؉ subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV ؉ subjects. This has clinical implications when using data from healthy volunteers to guide ART.

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“…Although interactions with drug transporters can be clinically insignificant, an awareness of potential transporter-related drug-drug be altered when co-administered with compounds which inhibit or induce P-glycoprotein. 3 The substrates of P-glycoprotein can be further divided into drugs which are not metabolised in humans, such as digoxin, and those which are substrates of both P-glycoprotein and drugmetabolising enzymes, particularly CYP3A4.…”

Section: Resultsmentioning

confidence: 99%