Drug-Drug Interactions at Organic Cation Transporter 1

The interaction between drugs and various transporters is one of the decisive factors that affect the pharmacokinetics and pharmacodynamics of drugs. The organic cation transporter 1 (OCT1) is a member of the Solute Carrier 22A (SLC22A) family that plays a vital role in the membrane transport of organic cations including endogenous substances and xenobiotics. This article mainly discusses the drug-drug interactions (DDIs) mediated by OCT1 and their clinical significance.

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Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1

Frontiers in Pharmacology ◽

10.3389/fphar.2020.607613 ◽

2021 ◽

Vol 11 ◽

Author(s):

Giuliano Ciarimboli

Keyword(s):

Organic Cation ◽

Basolateral Membrane ◽

Organic Cation Transporter ◽

Organic Cations ◽

Regulatory Processes ◽

Organic Cation Transporter 1 ◽

Exogenous Origin ◽

And Function

The organic cation transporter 1 (OCT1) belongs together with OCT2 and OCT3 to the solute carrier family 22 (SLC22). OCTs are involved in the movement of organic cations through the plasma membrane. In humans, OCT1 is mainly expressed in the sinusoidal membrane of hepatocytes, while in rodents, OCT1 is strongly represented also in the basolateral membrane of renal proximal tubule cells. Considering that organic cations of endogenous origin are important neurotransmitters and that those of exogenous origin are important drugs, these transporters have significant physiological and pharmacological implications. Because of the high expression of OCTs in excretory organs, their activity has the potential to significantly impact not only local but also systemic concentration of their substrates. Even though many aspects governing OCT function, interaction with substrates, and pharmacological role have been extensively investigated, less is known about regulation of OCTs. Possible mechanisms of regulation include genetic and epigenetic modifications, rapid regulation processes induced by kinases, regulation caused by protein–protein interaction, and long-term regulation induced by specific metabolic and pathological situations. In this mini-review, the known regulatory processes of OCT1 expression and function obtained from in vitro and in vivo studies are summarized. Further research should be addressed to integrate this knowledge to known aspects of OCT1 physiology and pharmacology.

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Emerging Clinical Importance of Hepatic Organic Cation Transporter 1 (OCT1) in Drug Pharmacokinetics, Dynamics, Pharmacogenetic Variability, and Drug Interactions

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.941 ◽

2017 ◽

Vol 103 (5) ◽

pp. 758-760 ◽

Cited By ~ 17

Author(s):

Maciej J. Zamek-Gliszczynski ◽

Kathleen M. Giacomini ◽

Lei Zhang

Keyword(s):

Drug Interactions ◽

Organic Cation ◽

Clinical Importance ◽

Organic Cation Transporter ◽

Organic Cation Transporter 1 ◽

Drug Pharmacokinetics

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Reduced Hepatic Uptake and Intestinal Excretion of Organic Cations in Mice with a Targeted Disruption of the Organic Cation Transporter 1 (Oct1 [Slc22a1]) Gene

Molecular and Cellular Biology ◽

10.1128/mcb.21.16.5471-5477.2001 ◽

2001 ◽

Vol 21 (16) ◽

pp. 5471-5477 ◽

Cited By ~ 171

Author(s):

Johan W. Jonker ◽

Els Wagenaar ◽

Carla A. A. M. Mol ◽

Marije Buitelaar ◽

Hermann Koepsell ◽

...

Keyword(s):

Organic Cation ◽

Basolateral Membrane ◽

Organic Cation Transporter ◽

Hepatic Uptake ◽

Organic Cations ◽

Wild Type ◽

Targeted Disruption ◽

Intestinal Excretion ◽

Organic Cation Transporter 1

ABSTRACT The polyspecific organic cation transporter 1 (OCT1 [SLC22A1]) mediates facilitated transport of small (hydrophilic) organic cations. OCT1 is localized at the basolateral membrane of epithelial cells in the liver, kidney, and intestine and could therefore be involved in the elimination of endogenous amines and xenobiotics via these organs. To investigate the pharmacologic and physiologic role of this transport protein, we generated Oct1 knockout (Oct1 −/−) mice.Oct1 −/− mice appeared to be viable, healthy, and fertile and displayed no obvious phenotypic abnormalities. The role of Oct1 in the pharmacology of substrate drugs was studied by comparing the distribution and excretion of the model substrate tetraethylammonium (TEA) after intravenous administration to wild-type and Oct1 −/− mice. InOct1 −/− mice, accumulation of TEA in liver was four to sixfold lower than in wild-type mice, whereas direct intestinal excretion of TEA was reduced about twofold. Excretion of TEA into urine over 1 h was 53% of the dose in wild-type mice, compared to 80% in knockout mice, probably because inOct1 −/− mice less TEA accumulates in the liver and thus more is available for rapid excretion by the kidney. In addition, we found that absence of Oct1 leads to decreased liver accumulation of the anticancer drug metaiodobenzylguanidine and the neurotoxin 1-methyl-4-phenylpyridium. In conclusion, our data show that Oct1 plays an important role in the uptake of organic cations into the liver and in their direct excretion into the lumen of the small intestine.

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