Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety

Paula Soria-Chacartegui; Pablo Zubiaur; Dolores Ochoa; Gonzalo Villapalos-García; Manuel Román; Miriam Matas; Laura Figueiredo-Tor; Gina Mejía-Abril; Sofía Calleja; Alejandro de Miguel; Marcos Navares-Gómez; Samuel Martín-Vilchez; Francisco Abad-Santos

doi:10.3390/pharmaceutics15020404

Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety

Pharmaceutics. 2023 Jan 25;15(2):404. doi: 10.3390/pharmaceutics15020404.

Authors

Affiliations

¹ Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), 28006 Madrid, Spain.
² Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Research Institute, Kansas City, MO 64102, USA.
³ Servicio de Bioquímica Clínica, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
⁴ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.

Abstract

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t_1/2) (univariate p-value (p_uv) = 0.039, multivariate p-value (p_mv) = 0.013, β = -5.31, R² = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC₇₂/DW) (p_uv = 0.025; p_mv = 0.026, β = 578.90, R² = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6, SLC22A1 and CYP3A4. In addition to the previous associations, CYP2D6 UMs showed a lower AUC₇₂/DW (p_uv = 0.046, p_mv = 0.049, β = -68.80, R² = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain (p_uv = 0.038) and dizziness (p_uv = 0.038, p_mv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1. Further research is needed to gather more evidence before its application in clinical practice.

Keywords: CYP2D6; SLC22A1; amlodipine; pharmacogenetics.

Grants and funding

P.S.-C. is financed by the FPI-UAM-2021 predoctoral fellowship. G.V.-G. is co-financed by Instituto de Salud Carlos III (ISCIII) and the European Social Fund (PFIS predoctoral grant, number FI20/00090). M.N.-G. is financed by the ICI20/00131 Grant, Acción Estratégica en Salud 2017–2020, ISCIII. P.Z. is financed by a “Contrato Margarita Salas de la convocatoria para la Recualificación del Sistema Universitario Español” (UAM).