The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1

Biochemical Pharmacology
Ali R SaadatmandMladen V Tzvetkov

Abstract

Debrisoquine is a probe drug for in vivo phenotyping of human CYP2D6 metabolic activity. However, debrisoquine is positively charged under physiological conditions and it is unclear how it enters the hepatocytes to undergo CYP2D6 metabolism. We analysed whether debrisoquine is a substrate of the hepatic organic cation transporter OCT1 and whether drug-drug interactions at OCT1, or polymorphisms in OCT1 gene, affect debrisoquine uptake. Debrisoquine showed low carrier-independent membrane permeability (P(e) of 0.01×10⁻⁶ cm/s in artificial PAMPA membranes) and strongly inhibited the uptake of the model OCT1 substrate MPP+ (IC₅₀ of 6.2 ± 0.8 μM). Debrisoquine uptake was significantly increased in HEK293 cells overexpressing OCT1 compared to control cells. The OCT1-mediated uptake of debrisoquine followed Michaelis-Menten kinetics (K(M) of 5.9 ± 1.5 μM and V(max) of 41.9 ± 4.5pmol/min/mg protein) and was inhibited by known OCT1 inhibitors and by commonly used drugs. OCT1-mediated debrisoquine uptake was reduced or missing in cells expressing loss-of-function OCT1 isoforms. Deletion of Met420 or substitution of Arg61Cys or Gly401Ser reduced V(max) by 48, 63 and 91%, respectively, but did not affect the K(M). The OCT1 isoforms carryi...Continue Reading

References

Sep 17, 1977·Lancet·A MahgoubR L Smith
Sep 1, 1979·European Journal of Clinical Pharmacology·M EichelbaumH J Dengler
Jan 1, 1978·British Journal of Clinical Pharmacology·J H SilasT R Marten
Jul 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·R C SkodaU A Meyer
Oct 1, 1985·Analytical Biochemistry·P K SmithD C Klenk
Dec 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·I JohanssonM Ingelman-Sundberg
Apr 1, 1996·European Journal of Drug Metabolism and Pharmacokinetics·A LlerenaJ Benítez
Jun 1, 1997·Molecular Pharmacology·L ZhangK M Giacomini
Jul 1, 1997·DNA and Cell Biology·V GorboulevH Koepsell
Feb 12, 1998·Biochemical and Biophysical Research Communications·J M GuidiceF Broly
Jan 27, 1998·Archives of Toxicology. Supplement. = Archiv Für Toxikologie. Supplement·H RaunioS Anttila
Apr 25, 2000·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·V A PereiraS R Santos
Mar 26, 2002·Journal of the American Society of Nephrology : JASN·Hideyuki MotohashiKen-Ichi Inui
Feb 28, 2003·Molecular Pharmacology·Dallas BednarczykStephen H Wright
Apr 30, 2003·Proceedings of the National Academy of Sciences of the United States of America·Yan ShuUNKNOWN Pharmacogenetics Of Membrane Transporters Investigators
Jun 18, 2003·Clinical Pharmacology and Therapeutics·Magnus ChristensenLeif Bertilsson
Apr 9, 2005·American Journal of Respiratory Cell and Molecular Biology·Katrin Susanne LipsHermann Koepsell
Nov 8, 2005·Drug Metabolism and Pharmacokinetics·Naoko KimuraKen-Ichi Inui
Jun 20, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yueying ZhenJeffrey R Idle
Sep 6, 2006·Clinical Pharmacology and Therapeutics·Nathalie K ZgheibRobert A Branch
May 4, 2007·The Journal of Clinical Investigation·Yan ShuKathleen M Giacomini
Jun 27, 2007·British Journal of Pharmacology·R MoaddelI W Wainer
Sep 16, 2008·Journal of Medicinal Chemistry·Gustav AhlinPer Artursson
Dec 24, 2008·Pharmacogenomics·Adrián LlerenaEva M Peñas-Lledó
May 12, 2009·Biochemical Pharmacology·Naoko KimuraKen-ichi Inui
Jul 11, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Anne T NiesElke Schaeffeler

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Citations

Jul 16, 2013·Current Opinion in Nephrology and Hypertension·Hermann Koepsell
Jul 19, 2013·Pharmacogenomics·Tsuyoshi FukudaSenthilkumar Sadhasivam
Nov 28, 2013·Pharmacogenomics·Jürgen Brockmöller, Mladen V Tzvetkov
Nov 4, 2015·The Pharmacogenomics Journal·C Arimany-NardiM Pastor-Anglada
Jun 19, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·David J WagnerJoanne Wang
Apr 17, 2018·Journal of Personalized Medicine·Elisa LozanoElisa Herraez
Sep 27, 2014·American Journal of Therapeutics·Omar T HassanRohit R Arora
Dec 14, 2018·Journal of Personalized Medicine·Kristin BokelmannMladen V Tzvetkov
Dec 14, 2017·PloS One·Marleen Julia MeyerMladen Vassilev Tzvetkov
Dec 20, 2019·Pharmacological Reviews·Hermann Koepsell
Oct 14, 2020·Expert Opinion on Drug Metabolism & Toxicology·Matthijs W van HoogdalemTomoyuki Mizuno
Jun 22, 2021·Frontiers in Pharmacology·Marleen J Meyer, Mladen V Tzvetkov
Oct 10, 2019·Journal of Medicinal Chemistry·Marleen J MeyerMladen V Tzvetkov

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