ATP-binding cassette transporter polymorphisms and the pharmacokinetics of oral esketamine
Pharmacogenomics – December 12, 2025
Source: OpenAlex
Summary
Oral esketamine shows promise for treating resistant depression, yet genetic variations may affect its effectiveness. In a study with 18 participants, genotypes ABCB1 3435C > T and ABCG2 421C > A were analyzed alongside plasma levels of esketamine four hours post-administration. Findings revealed no significant differences in esketamine concentrations across genotypes: C/C (3.8 µg/L), C/T (2.7 µg/L), and T/T (1.0 µg/L) for ABCB1; and C/A (1.5 µg/L) versus C/C (2.4 µg/L) for ABCG2. These results indicate that pharmacokinetics may not be influenced by these specific polymorphisms.
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).