Bedeutung von Genvarianten im organischen Kationentransporter 1 (OCT1) für Pharmakokinetik, Wirkungen und Nebenwirkungen des Antidepressivums Amitriptylin und dessen Metaboliten Nortriptylin

Meaning of genetic variants in the organic cation transporter 1 (OCT1) for pharmacokinetics, effects and side effects of the antidepressant Amitriptyline and its metabolite Nortriptyline

by Maria Kullmann
Doctoral thesis
Date of Examination:2024-07-16
Date of issue:2024-07-09
Advisor:Dr. Johannes Matthaei
Referee:Prof. Dr. Jürgen Brockmöller
Referee:Prof. Dr. Dirk Wedekind
Persistent Address: http://dx.doi.org/10.53846/goediss-10604

 

 

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Abstract

English

Efficacy and side effects of amitriptyline and nortriptyline vary greatly between patients. Interindividual pharmacokinetic variability may be based on genetic polymorphisms in the drug metabolizing enzymes CYP2C19 and CYP2D6, but there is still unexplained variability. One possible explanation could be variable hepatocellular uptake. Literature data suggest that the organic cation transporter OCT1 may mediate liver cell uptake of antidepressants like amitriptyline and nortriptyline. We analyzed the impact of OCT1 on hepatocellular uptake, pharmacokinetics, and clinical effects of amitriptyline and nortriptyline in 35 healthy human volunteers preselected for their OCT1 genotypes. 25 mg of amitriptyline was orally administered, and the area under the curve was statistically evaluated. In this study, OCT1 genetic polymorphism had no significant effects on amitriptyline and nortriptyline pharmacokinetics. In contrast, the strong impact of the CYP2D6 genotype on both substances and of the CYP2C19 on nortriptyline was confirmed. However, this had no effect on the side effects. Overall, amitriptyline was well tolerated. Unfortunately, severe fatigue could be detected even at a low dose. In conclusion, OCT1 activity may have no impact on the pharmacokinetics of amitriptyline and nortriptyline. Further studies must be elucidate which organic cation transporters or other transport mechanism are relevant for their hepatic uptake.
Keywords: CYP2C19; CYP2D6; OCT1; amitriptyline; drug transport; nortriptyline; organic cation transporter 1
 
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