Effects of genetic polymorphisms in the organic cation transporter OCT1 on cellular uptake and metabolism of antidepressants and other drugs
Final Report Abstract
The main aim of this project was to identify clinically relevant drugs, which are influenced in their pharmacokinetics and consequently in their intended and adverse effects by the highly genetically polymorphic transporter OCT1. Further aims were to contribute to a better understanding of genotype-to-phenotype relationships of the naturally existing protein variants in OCT1 and to contribute to the understanding of the regulation of OCT1 expression. In brief, the following major results were obtained: • We could show that OCT1 is a clinically relevant hepatic transporter and OCT1 polymorphisms affect the pharmacokinetics of the antimigraine drug sumatriptan, the opioids tramadol and morphine. We have also strong indication that OCT1 polymorphisms affect the adverse effects of the (12-sympatomemetic drug fenoterol: an observation that may be of high therapeutic relevance. In contrast, the antidepressant desvenlafaxine and the antimalarial drug proguanil are clearly transported into the cell by OCT1 in vivo, but OCT1 polymorphisms have only limited effects on the pharmacokinetics of these drugs in humans. • Several coding OCT1 polymorphisms, including the most common deletion of methionine420, M420del, showed highly substrate-specific effects on OCT1 activity. These were observed not only in vitro, but also in vivo. Thus, these findings are not only interesting for a better understanding of the structure-to-function relation of OCT1, but may be of therapeutic relevance. • Extensive functional analyses of polymorphisms in the promotor of OCT1 showed that the wide variation in OCT1 expression is not due to inherited polymorphisms in the canonical core promotor. However, using evolutionary conservation analyses we identified a new transcriptional regulatory region in intron 1 of the OCT1 gene. Genetic polymorphisms in this region remain to be evaluated in respect to effects on OCT1 expression, but alternative causes of the strong inter-individual variability like epigenetic effects or effects of trans-acting genetic polymorphisms on OCT1 expression should also be considered. • Comprehensive analyses of numerous drugs studied in vitro and in vivo as part of the present project enable us to predict clinically relevant substrates of OCT1. Evaluating drug chemistry and routes of elimination we can identify drugs that are substrates of OCT1 and OCT1 polymorphisms may play a role in humans. However, further studies are needed to understand some notable exemptions from this rule (e.g. desvenlafaxine and proguanil).
Publications
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(2013) “Hepatocyte nuclear factor 1 regulates the expression of the organic cation transporter 1 via binding to an evolutionary conserved region in intron 1 of the OCT1 gene.” J Pharmacol Exp Ther. 347(1):181-92
O'Brien V.P., Bokelmann K., Ramírez J., Jobst K., Ratain M.J., Brockmöller J., Tzvetkov M.V.
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(2013) „Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. “ Biochem Pharmacol. 86(5):666-78
Tzvetkov M.V., Dos Santos Pereira J.N., Meineke I., Saadatmand A.R., Stingl J.C., Brockmöller J.
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(2014) “The role of membrane transporters in the pharmacokinetics of psychotropic drugs: in vitro studies with special focus on organic cation transporters” Georg-August-University, PhD Program Molecular Medicine
Joao Nuno dos Santos Pereira
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(2015) „Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1.” Genome medicine 7:56
Seitz T., Stalmann R., Dalila N., Chen J., Pojar S., Dos Santos Pereira J.N., Krätzner R., Brockmöller J., and Tzvetkov M.V.
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„Functional characterization of the genetic polymorphisms in the OCT1 promoter”, Jahrestagung der DGPT, Kiel, March 2015
Bokelmann K., Brockmoller J., Tzvetkov M.V.
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(2016) “Functional characterization of genetic polymorphisms in the organic cation transporter OCT1 with a special focus on the substrate-specific effects of the M420del polymorphism” Georg-August-University, PhD Program Molecular Medicine
Tina Seitz
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(2016) “OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics.“ Clinical pharmacology and therapeutics 99(6):633-41
Matthaei J., Kuron D., Faltraco F., Knoch T., Dos Santos Pereira J.N., Abu Abed M., Prukop T., Brockmöller J., and Tzvetkov M.V.
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Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption. Pain, November 2016 - Volume 157 - Issue 11 - p 2467–2475
Stamer U.M., Musshoff F., Stüber F., Brockmöller J., Steffens M., Tzvetkov M.V.
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“Effects of genetic polymorphisms in the organic cation transporter OCT1 on desvenlafaxine pharmacokinetics in healthy volunteers.” Jahrestagung der DGPT, Berlin, March 2016
Matthaei J., Prukop T., Faltraco F., Krepinsky G., Abu Abed M., Brockmoller J., Tzvetkov M. V.
