ATP-binding cassette transporter polymorphisms and the pharmacokinetics of oral esketamine
Jerome Oude Nijhuis, Daniël T. Coerts, Jens van Dalfsen, Sanne Y. Smith-Apeldoorn, Jolien K. E. Veraart, Robert Schoevers, Daan Touw, Ron van Schaik, Wim J. Tamminga
Pharmacogenomics December 12, 2025 DOI: 10.1080/14622416.2026.2617376 via OpenAlex
Summary
AI-generated from the abstractOral esketamine is a promising treatment for depression that does not respond to other therapies, but how much of the drug reaches the bloodstream varies from person to person. This study tested whether common genetic variations in two drug-transport proteins, ABCB1 and ABCG2, affect esketamine levels in the blood. In 18 participants from a placebo-controlled trial, esketamine concentrations four hours after dosing did not differ significantly among people with different ABCB1 or ABCG2 genotypes. Metabolite levels also showed no association with these genetic variants. The findings suggest that these transporter polymorphisms do not influence oral esketamine pharmacokinetics, though the small sample size means the results are preliminary and need confirmation in larger studies.
Study at a glance
| Characteristics | Randomized controlled trial Placebo-controlled Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Adults with treatment-resistant depression |
| Intervention | oral esketamine |
| Dose | low dose |
| Topics | Ketamine |
| Keywords | Pharmacokinetics Pharmacogenetics Genotype Genotyping Active metabolite |
| Key finding | ABCB1 and ABCG2 transporter polymorphisms were not significantly associated with plasma concentrations of esketamine or its metabolites four hours after oral dosing. |
Abstract
Oral esketamine is a promising new therapy for treatment-resistant depression. However, concerns exist about interindividual pharmacokinetic variability. Genetic polymorphisms regulating the expression of ATP-binding cassette (ABC) transporters might influence bioavailability. Utilizing blood samples from a placebo-controlled trial investigating repeated, low dose oral esketamine (N = 18), we performed ABCB1 3435C > T and ABCG2 421C > A genotyping and measured the plasma levels of esketamine and its metabolites 4 h after dosing. For ABCB1 3435C > T, esketamine concentrations for C/C (Mdn = 3.8 µg/L), C/T (Mdn = 2.7 µg/L), and T/T (Mdn = 1.0 µg/L) were not significantly different (χ2(2) = 3.41, p = 0.182). For ABCG2 421C > A, esketamine concentrations did not differ significantly between C/A (Mdn = 1.5 µg/L) and C/C (Mdn = 2.4 µg/L) (U = 10.00, p = 0.471). Metabolite plasma concentrations were also not associated with polymorphism status. These results suggest that oral esketamine pharmacokinetics are unaffected by ABC transporter polymorphisms. However, due to the limited sample size and genotype variant representation, results are preliminary. Larger, more adequately powered studies are needed to clarify genotype effects and inform individualized esketamine therapyClinical trial registration: NTR6161 (Dutch Trial Register).