Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients

Abstract

The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms.

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review

“…However, this study did not detect any relation between the amitriptyline pharmacodynamics and CYP2C19 or CYP2D6 [88]. Additionally, Matthaei et al reported that a decrease in the activity of CYP2D6 led to an increase in the amitriptyline plasma concentration [92]. However, there were only a limited number of studies investigating the impact of genetic variation on the efficacy of amitriptyline in neuropathic pain reduction.…”

“…Several studies have indicated a possible impact of pharmacogenetically relevant SNPs on the pharmacokinetics of the drug. Matthaei et al [92] investigated a possible association between organic cation transporter 1 (OCT1, SLC22A1) polymorphisms and the pharmacokinetics of amitriptyline and nortriptyline. This study detected a two times higher the time of the maximum plasma concentration (T max ) in the volunteers with two active OCT1 alleles (OCT1*1) compared to those who were carriers of one active allele (OCT1*1) and one inactive or reduced activity allele (OCT1*2, 3*, 4*) and subjects who carried two inactive or reduced activity alleles (OCT1*2, *3, *4, *5).…”

Substrates of the Human Brain Proton-Organic Cation Antiporter and Comparison with Organic Cation Transporter 1 Activities

“…In this respect, the so-called trans-stimulation assay (data for all 72 substances tested in Table 4 ) may be less dependent on lipophilicity. Indeed, lipophilic substances such as amitriptyline or its metabolite nortriptyline, which are not OCT1 substrates [ 22 ], had a reasonable intrinsic clearance as measured by influx into the hCMEC/D3 cells ( Table 3 ). These data also indicate that overrunning carrier-mediated transports by simple diffusion in both directions cannot be the only explanation why OCT1 substrates are typically not highly lipophilic.…”

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

“…16,20 N 1methylnicotinamide (NMN), a metabolite of niacin, is reported to be an endogenous biomarker for assessing renal MATE1, MATE2K, and OCT2 activity, 18,20,21 whereas isobutyryl-Lcarnitine (IBC) has been proposed as a potential surrogate for the evaluation of hepatic OCT1 activity. 16,22,23 In this paper, we describe a series of preclinical in vitro and phase I clinical studies conducted to evaluate the potential effect of abrocitinib on drug transporter inhibition by assessing the pharmacokinetics of dabigatran etexilate, rosuvastatin, metformin, and endogenous biomarkers. Dabigatran etexilate is a sensitive substrate of intestinal P-gp and is the prodrug of the direct thrombin inhibitor, dabigatran.…”

“…Using endogenous rather than exogeneous substrates as probes reduces the pill burden on participants, can enable the assessment of multiple transporters within the same clinical study, and may eliminate the need to conduct a standalone clinical DDI study entirely 16,20 . N 1 ‐methylnicotinamide (NMN), a metabolite of niacin, is reported to be an endogenous biomarker for assessing renal MATE1, MATE2K, and OCT2 activity, 18,20,21 whereas isobutyryl‐ L ‐carnitine (IBC) has been proposed as a potential surrogate for the evaluation of hepatic OCT1 activity 16,22,23 …”