Pharmacogenetics of OATP (
 SLC21
 /
 SLCO
 ), OAT and OCT (
 SLC22
 ) and PEPT (
 SLC15
 ) Transporters in the Intestine, Liver and Kidney

Zaïr, Zoulikha M.; Eloranta, Jyrki J.; Stieger, Bruno; Kullak‐Ublick, Gerd A.

doi:10.2217/14622416.9.5.597

Cited by 104 publications

(67 citation statements)

References 109 publications

(105 reference statements)

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“…[1][2][3] These membrane transporters also crucially contribute to drug delivery and response when hepatocytes are the pharmacological target cells. Variable transporter expression may contribute to interindividual variation in response to certain drugs.…”

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confidence: 99%

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

et al. 2009

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An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

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confidence: 99%

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

et al. 2009

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“…This latter point is illustrated by the observations that Nieman-Pick C1-like 1 protein is located in the apical membrane of enterocytes and involved in cholesterol absorption [5] or that uptake of very long-chain fatty acids into peroxisomes involves the role of the ATP binding cassette (ABC) transporter ABCD1 [6] (see table 1 for a list of transporters and their subcellular expression covered in this review). The number of drug transporters is high and the knowledge on their pharmacogenetics is rapidly evolving [7][8][9][10][11][12][13][14][15].…”

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confidence: 99%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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“…Всасываясь в энтероцит, молекула лекарства может двигаться как путем пассивной диффузии, так и подвергаться действию ряда специфических белковых транспортеров и ферментов [8][9][10][11]. После возможных метаболических превращений в клетке оставшаяся часть лекарства выходит из неё на базолатеральную (наружную) сторону, с последующим поступлением в системную циркуляцию -или через портальную вену и печень, или, в значительно меньшей степени, непосредственно, через лимфатическую систему [12].…”

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Bioavailability of oral drug formulations and methods for its improvement

et al. 2010

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The recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations. The current review deals with the processes occurring at the gastro-intestinal (GI) tract and their influence on the drug form. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. They include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in the GI tract, dispersed forms with surface-active soluble polymers, micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of drug indomethacin in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug forms, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical forms that increase the bioavailability of the drugs.

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Pharmacogenetics of OATP ( SLC21 / SLCO ), OAT and OCT ( SLC22 ) and PEPT ( SLC15 ) Transporters in the Intestine, Liver and Kidney

Cited by 104 publications

References 109 publications

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

Expression of Organic Cation Transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) Is Affected by Genetic Factors and Cholestasis in Human Liver†

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Bioavailability of oral drug formulations and methods for its improvement

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