Characterization of cytochrome P450 (CYP) 2D6 drugs as substrates of human organic cation transporters and multidrug and toxin extrusion proteins.
CYP2D6
MATE1
MATE2K
OCT1
OCT2
OCT3
adverse drug reaction
pharmacogenetics
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
04
05
2020
revised:
24
11
2020
accepted:
21
12
2020
pubmed:
13
1
2021
medline:
6
7
2021
entrez:
12
1
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
Cations
0
Organic Cation Transport Proteins
0
Organic Cation Transporter 2
0
Pharmaceutical Preparations
0
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1459-1474Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : Germany's Excellence Strategy - EXC 2180 - 390900677
Organisme : Robert Bosch Stiftung, Stuttgart
Organisme : Interfaculty Centre for Pharmacogenomics and Pharma Research (ICEPHA) Graduate Program, University of Tuebingen
Informations de copyright
© 2021 The British Pharmacological Society.
Références
Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., … Davies, J. A. (2019). The Concise Guide to PHARMACOLOGY 2019/20. British Journal of Pharmacology, 176(Suppl 1), S297-S396. https://doi.org/10.1111/bph.14752
Alexander, S. P. H., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., … Davies, J. A. (2019). The Concise Guide to PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology, 176(Suppl 1), S397-S493. https://doi.org/10.1111/bph.14753
Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., … Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology. British Journal of Pharmacology, 175(3), 407-411. https://doi.org/10.1111/bph.14112
Barclay, M. L., Sawyers, S. M., Begg, E. J., Zhang, M., Roberts, R. L., Kennedy, M. A., & Elliott, J. M. (2003). Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics, 13(10), 627-632. https://doi.org/10.1097/01.fpc.0000054129.14659.ef
Brouwer, K. L., Keppler, D., Hoffmaster, K. A., Bow, D. A., Cheng, Y., Lai, Y., … Evers, R. (2013). In vitro methods to support transporter evaluation in drug discovery and development. Clinical Pharmacology and Therapeutics, 94(1), 95-112. https://doi.org/10.1038/clpt.2013.81
Chen, J., Brockmöller, J., Seitz, T., König, J., Tzvetkov, M. V., & Chen, X. (2017). Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22 (OCT) and the SLC47 (MATE) families. Biological Chemistry, 398(2), 237-249. https://doi.org/10.1515/hsz-2016-0236
Chen, J.-Y., Brockmöller, J., Tzvetkov, M. V., Wang, L.-J., & Chen, X.-J. (2019). An in vitro study on interaction of anisodine and monocrotaline with organic cation transporters of the SLC22 and SLC47 families. Chinese Journal of Natural Medicines, 17(7), 490-497. https://doi.org/10.1016/S1875-5364(19)30070-6
Chen, L., Shu, Y., Liang, X., Chen, E. C., Yee, S. W., Zur, A. A., … Giacomini, K. M. (2014). OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proceedings of the National Academy of Sciences of the United States of America, 111(27), 9983-9988. https://doi.org/10.1073/pnas.1314939111
Chen, Y., Li, S., Brown, C., Cheatham, S., Castro, R. A., Leabman, M. K., … Giacomini, K. M. (2009). Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenetics and Genomics, 19(7), 497-504. https://doi.org/10.1097/FPC.0b013e32832cc7e9
Cho, S. K., & Chung, J. Y. (2016). The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment. International Journal of Clinical Pharmacology and Therapeutics, 54(4), 253-262. https://doi.org/10.5414/CP202473
Choi, J. H., Yee, S. W., Ramirez, A. H., Morrissey, K. M., Jang, G. H., Joski, P. J., … Giacomini, K. M. (2011). A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clinical Pharmacology and Therapeutics, 90(5), 674-684. https://doi.org/10.1038/clpt.2011.165
Chong, C.-R., Sallustio, B., & Horowitz, J. D. (2016). Drugs that affect cardiac metabolism: Focus on perhexiline. Cardiovascular Drugs and Therapy, 30(4), 399-405. https://doi.org/10.1007/s10557-016-6664-3
Curtis, M. J., Alexander, S., Cirino, G., Docherty, J. R., George, C. H., Giembycz, M. A., … Ahluwalia, A. (2018). Experimental design and analysis and their reporting II: Updated and simplified guidance for authors and peer reviewers. British Journal of Pharmacology, 175(7), 987-993. https://doi.org/10.1111/bph.14153
Eichelbaum, M., Ingelman-Sundberg, M., & Evans, W. E. (2006). Pharmacogenomics and individualized drug therapy. Annual Review of Medicine, 57, 119-137. https://doi.org/10.1146/annurev.med.56.082103.104724
Eichelbaum, M., Spannbrucker, N., & Dengler, H. J. (1979). Influence of the defective metabolism of sparteine on its pharmacokinetics. European Journal of Clinical Pharmacology, 16(3), 189-194. https://doi.org/10.1007/bf00562060
Eichelbaum, M., Spannbrucker, N., Steincke, B., & Dengler, H. J. (1979). Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. European Journal of Clinical Pharmacology, 16(3), 183-187. https://doi.org/10.1007/BF00562059
Elston, R. C., & Forthofer, R. (1977). Testing for Hardy-Weinberg equilibrium in small samples. Biometrics, 33(3), 536-542. https://doi.org/10.2307/2529370
Emami Riedmaier, A., Burk, O., van Eijck, B. A., Schaeffeler, E., Klein, K., Fehr, S., … Nies, A. T. (2016). Variability in hepatic expression of organic anion transporter 7/SLC22A9, a novel pravastatin uptake transporter: Impact of genetic and regulatory factors. The Pharmacogenomics Journal, 16(4), 341-351. https://doi.org/10.1038/tpj.2015.55
Fux, R., Mörike, K., Pröhmer, A. M. T., Delabar, U., Schwab, M., Schaeffeler, E., … Kivistö, K. T. (2005). Impact of genotype on adverse effects during treatment with metoprolol: A prospective clinical study. Clinical Pharmacology & Therapeutics, 78(4), 378-387. https://doi.org/10.1016/j.clpt.2005.07.004
Gaedigk, A., Ingelman-Sundberg, M., Miller, N. A., Leeder, J. S., Whirl-Carrillo, M., & Klein, T. E. (2018). The Pharmacogene variation (PharmVar) consortium: Incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clinical Pharmacology and Therapeutics, 103(3), 399-401. https://doi.org/10.1002/cpt.910
Giacomini, K. M., Huang, S. M., Tweedie, D. J., Benet, L. Z., Brouwer, K. L., Chu, X., … Zhang, L. (2010). Membrane transporters in drug development. Nature Reviews. Drug Discovery, 9(3), 215-236. https://doi.org/10.1038/nrd3028
Griese, E. U., Zanger, U. M., Brudermanns, U., Gaedigk, A., Mikus, G., Morike, K., … Stüven, T. (1998). Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics, 8(1), 15-26. https://doi.org/10.1097/00008571-199802000-00003
Hastings, J., de Matos, P., Dekker, A., Ennis, M., Harsha, B., Kale, N., … Steinbeck, C. (2013). The ChEBI reference database and ontology for biologically relevant chemistry: Enhancements for 2013. Nucleic Acids Research, 41(Database issue), D456-D463. https://doi.org/10.1093/nar/gks1146
Hendrickx, R., Johansson, J. G., Lohmann, C., Jenvert, R. M., Blomgren, A., Borjesson, L., & Gustavsson, L. (2013). Identification of novel substrates and structure activity relationship of cellular uptake mediated by the human organic cation transporters 1 and 2 (hOCT1 and hOCT2). Journal of Medicinal Chemistry, 56(18), 7232-7242. https://doi.org/10.1021/jm400966v
Ito, S., Kusuhara, H., Yokochi, M., Toyoshima, J., Inoue, K., Yuasa, H., & Sugiyama, Y. (2012). Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. The Journal of Pharmacology and Experimental Therapeutics, 340(2), 393-403. https://doi.org/10.1124/jpet.111.184986
Kerb, R., Brinkmann, U., Chatskaia, N., Gorbunov, D., Gorboulev, V., Mornhinweg, E., … Koepsell, H. (2002). Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics, 12(8), 591-595. https://doi.org/10.1097/00008571-200211000-00002
Kévorkian, J. P., Michel, C., Hofmann, U., Jacqz-Aigrain, E., Kroemer, H. K., Peraldi, M. N., … Funck-Brentano, C. (1996). Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: Comparison of sparteine and dextromethorphan. Clinical Pharmacology & Therapeutics, 59(5), 583-592. https://doi.org/10.1016/S0009-9236(96)90187-3
Killalea, S. M., & Krum, H. (2001). Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease. American Journal of Cardiovascular Drugs, 1(3), 193-204. https://doi.org/10.2165/00129784-200101030-00005
Kimura, N., Masuda, S., Katsura, T., & Inui, K. (2009). Transport of guanidine compounds by human organic cation transporters, hOCT1 and hOCT2. Biochemical Pharmacology, 77(8), 1429-1436. https://doi.org/10.1016/j.bcp.2009.01.010
Koepsell, H. (2019). Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs. Biological Chemistry, 400(2), 195-207. https://doi.org/10.1515/hsz-2018-0191
Liang, X., Yee, S. W., Chien, H.-C., Chen, E. C., Luo, Q., Zou, L., … Giacomini, K. M. (2018). Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content. PLoS Biology, 16(4), e2002907. https://doi.org/10.1371/journal.pbio.2002907
Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R., & Smith, R. L. (1977). Polymorphic hydroxylation of debrisoquine in man. The Lancet, 2(8038), 584-586. https://doi.org/10.1016/s0140-6736(77)91430-1
Matsson, P., Fenu, L. A., Lundquist, P., Wisniewski, J. R., Kansy, M., & Artursson, P. (2015). Quantifying the impact of transporters on cellular drug permeability. Trends in Pharmacological Sciences, 36(5), 255-262. https://doi.org/10.1016/j.tips.2015.02.009
Minematsu, T., Iwai, M., Umehara, K. I., Usui, T., & Kamimura, H. (2010). Characterization of human organic cation transporter 1 (OCT1/SLC22A1)-, and OCT2 (SLC22A2)-mediated transport of YM155 monobromide, a novel survivin suppressant. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 38, 1-4. https://doi.org/10.1124/dmd.109.028142
Mörike, K., Kivistö, K. T., Schaeffeler, E., Jägle, C., Igel, S., Drescher, S., … Schwab, M. (2008). Propafenone for the prevention of atrial tachyarrhythmias after cardiac surgery: A randomized, double-blind placebo-controlled trial. Clinical Pharmacology & Therapeutics, 84(1), 104-110. https://doi.org/10.1038/sj.clpt.6100473
Motohashi, H., & Inui, K.-I. (2016). Pharmacological and toxicological significance of the organic cation transporters OCT and MATE: Drug disposition, interaction and toxicity. In G. Ciarimboli, S. Gautron, & E. Schlatter (Eds.), Organic cation transporters (pp. 73-92). Cham: Springer. https://doi.org/10.1007/978-3-319-23793-0_3
Nies, A. T., Damme, K., Kruck, S., Schaeffeler, E., & Schwab, M. (2016). Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Archives of Toxicology, 90(7), 1555-1584. https://doi.org/10.1007/s00204-016-1728-5
Nies, A. T., Hofmann, U., Resch, C., Schaeffeler, E., Rius, M., & Schwab, M. (2011). Proton pump inhibitors inhibit metformin uptake by organic cation uptake transporters (OCTs). PLoS ONE, 6(7), e22163. https://doi.org/10.1371/journal.pone.0022163
Nies, A. T., Koepsell, H., Damme, K., Schwab, M., Fromm, M. F., & Kim, R. B. (2011). Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Drug Transporters, 201, 105-167. https://doi.org/10.1007/978-3-642-14541-4_3
Nies, A. T., Koepsell, H., Winter, S., Burk, O., Klein, K., Kerb, R., … Schaeffeler, E. (2009). Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology (Baltimore, Md.), 50(4), 1227-1240. https://doi.org/10.1002/hep.23103
Nies, A. T., Schaeffeler, E., van der Kuip, H., Cascorbi, I., Bruhn, O., Kneba, M., … Schwab, M. (2014). Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 20(4), 985-994. https://doi.org/10.1158/1078-0432.CCR-13-1999
Obianom, O. N., Coutinho, A. L., Yang, W., Yang, H., Xue, F., & Shu, Y. (2017). Incorporation of a biguanide scaffold enhances drug uptake by organic cation transporters 1 and 2. Molecular Pharmaceutics, 14(8), 2726-2739. https://doi.org/10.1021/acs.molpharmaceut.7b00285
Radovanovic, D., Meier, P. J., Guirguis, M., Lorent, J. P., & Kupferschmidt, H. (2000). Dose-dependent toxicity of diphenhydramine overdose. Human & Experimental Toxicology, 19(9), 489-495. https://doi.org/10.1191/096032700671040438
Raimundo, S., Toscano, C., Klein, K., Fischer, J., Griese, E. U., Eichelbaum, M., … Zanger, U. M. (2004). A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects. Clinical Pharmacology and Therapeutics, 76(2), 128-138. https://doi.org/10.1016/j.clpt.2004.04.009
Saadatmand, A. R., Tadjerpisheh, S., Brockmoller, J., & Tzvetkov, M. V. (2012). The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1. Biochemical Pharmacology, 83(10), 1427-1434. https://doi.org/10.1016/j.bcp.2012.01.032
Schärfe, C. P. I., Tremmel, R., Schwab, M., Kohlbacher, O., & Marks, D. S. (2017). Genetic variation in human drug-related genes. Genome Medicine, 9(1), 117. https://doi.org/10.1186/s13073-017-0502-5
Seitz, T., Stalmann, R., Dalila, N., Chen, J., Pojar, S., dos Santos Pereira, J. N., … Tzvetkov, M. V. (2015). Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1. Genome Medicine, 7(1), 56. https://doi.org/10.1186/s13073-015-0172-0
Shah, A., Yousuf, T., Ziffra, J., Zaidi, A., & Raghuvir, R. (2015). Diphenhydramine and QT prolongation-A rare cardiac side effect of a drug used in common practice. Journal of Cardiology Cases, 12(4), 126-129. https://doi.org/10.1016/j.jccase.2015.06.002
Shu, Y., Brown, C., Castro, R., Shi, R., Lin, E., Owen, R., … Giacomini, K. M. (2008). Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clinical Pharmacology and Therapeutics, 83(2), 273-280. https://doi.org/10.1038/sj.clpt.6100275
Shu, Y., Leabman, M. K., Feng, B., Mangravite, L. M., Huang, C. C., Stryke, D., … Giacomini, K. M. (2003). Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proceedings of the National Academy of Sciences of the United States of America, 100(10), 5902-5907. https://doi.org/10.1073/pnas.0730858100
Shu, Y., Sheardown, S. A., Brown, C., Owen, R. P., Zhang, S., Castro, R. A., … Giacomini, K. M. (2007). Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. The Journal of Clinical Investigation, 117(5), 1422-1431. https://doi.org/10.1172/JCI30558
Sicari, V., & Zabbo, C. P. (2020). Diphenhydramine. Treasure Island (FL). StatPearls Publishing LLC. https://pubmed.ncbi.nlm.nih.gov/30252266/
Silas, J. H., Lennard, M. S., Tucker, G. T., Smith, A. J., Malcolm, S. L., & Marten, T. R. (1978). The disposition of debrisoquine in hypertensive patients. British Journal of Clinical Pharmacology, 5(1), 27-34. https://doi.org/10.1111/j.1365-2125.1978.tb01594.x
Simasek, M., & Blandino, D. A. (2007). Treatment of the common cold. American Family Physician, 75(4), 515-520.
Teft, W. A., Morse, B. L., Leake, B. F., Wilson, A., Mansell, S. E., Hegele, R. A., … Kim, R. B. (2017). Identification and characterization of trimethylamine-N-oxide uptake and efflux transporters. Molecular Pharmaceutics, 14(1), 310-318. https://doi.org/10.1021/acs.molpharmaceut.6b00937
Tzvetkov, M. V., Matthaei, J., Pojar, S., Faltraco, F., Vogler, S., Prukop, T., … Brockmöller, J. (2018). Increased systemic exposure and stronger cardiovascular and metabolic adverse reactions to fenoterol in individuals with heritable OCT1 deficiency. Clinical Pharmacology and Therapeutics, 103(5), 868-878. https://doi.org/10.1002/cpt.812
Winter, S., Fisel, P., Büttner, F., Rausch, S., D'Amico, D., Hennenlotter, J., … Schaeffeler, E. (2016). Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes. Scientific Reports, 6, 29930. https://doi.org/10.1038/srep29930
Wright, S. H. (2019). Molecular and cellular physiology of organic cation transporter 2. American Journal of Physiology. Renal Physiology. Advance Online Publication, 317, F1669-F1679. https://doi.org/10.1152/ajprenal.00422.2019
Yee, S. W., Brackman, D. J., Ennis, E. A., Sugiyama, Y., Kamdem, L. K., Blanchard, R., … Giacomini, K. M. (2018). Influence of transporter polymorphisms on drug disposition and response: A perspective from the International Transporter Consortium. Clinical Pharmacology and Therapeutics, 104(5), 803-817. https://doi.org/10.1002/cpt.1098
Zanger, U. M., Raimundo, S., & Eichelbaum, M. (2004). Cytochrome P450 2D6: Overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedeberg's Archives of Pharmacology, 369(1), 23-37. https://doi.org/10.1007/s00210-003-0832-2
Zanger, U. M., & Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics, 138(1), 103-141. https://doi.org/10.1016/j.pharmthera.2012.12.007
Zawertailo, L. A., Kaplan, H. L., Busto, U. E., Tyndale, R. F., & Sellers, E. M. (1998). Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: A pilot study. Journal of Clinical Psychopharmacology, 18(4), 332-337. https://doi.org/10.1097/00004714-199808000-00014
Zhou, Y., Ingelman-Sundberg, M., & Lauschke, V. M. (2017). Worldwide distribution of cytochrome P450 alleles: A meta-analysis of population-scale sequencing projects. Clinical Pharmacology and Therapeutics, 102(4), 688-700. https://doi.org/10.1002/cpt.690
Ziesenitz, V. C., & van den Anker, J. N. (2019). Psychiatrisches Krankheitsbild oder unerwünschte Arzneimittelwirkung?-Wie die CYP2D6-Aktivität eine dextromethorphan-Vergiftung hervorrufen kann [Psychiatric disorder or adverse drug reaction?-How CYP2D6 metabolizing activity can result in dextromethorphan intoxication]. Klinische Pädiatrie, 231(1), 46-48. https://doi.org/10.1055/a-0627-7462
Zolk, O., Solbach, T. F., König, J., & Fromm, M. F. (2009). Functional characterization of the human organic cation transporter 2 variant p.270Ala>Ser. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 37(6), 1312-1318. https://doi.org/10.1124/dmd.108.023762