Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins
| العنوان: | Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins |
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| المؤلفون: | Anne T. Nies, Elke Schaeffeler, Kathrin Klein, Kathleen M. Giacomini, Michel Eichelbaum, Matthias Schwab, Ute Hofmann, Claudia Neul, Stefan Winter |
| المصدر: | British Journal of Pharmacology. 178:1459-1474 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, CYP2D6, SLC47A1, Organic Cation Transport Proteins, Pharmacology, Hydroxylation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cations, medicine, Humans, Organic cation transport proteins, biology, Chemistry, Sparteine, Organic Cation Transporter 2, Cytochrome P450, Phenotype, 030104 developmental biology, Cytochrome P-450 CYP2D6, Pharmaceutical Preparations, Debrisoquine, Perhexiline, biology.protein, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Background and purpose The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine. Experimental approach OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1-, and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype. Key results OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype. Conclusions and implications Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs. |
| تدمد: | 1476-5381 0007-1188 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b9d3555d075053f2fad1daf3c8541155Test https://doi.org/10.1111/bph.15370Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b9d3555d075053f2fad1daf3c8541155 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765381 00071188 |
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