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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 <i>p</i>-value (<i>p</i>_uv) = 0.039, multivariate <i>p</i>-value (<i>p</i>_mv) = 0.013, β = −5.31, R² = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). <i>SLC22A1</i> rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC₇₂/DW) (<i>p</i>_uv = 0.025; <i>p</i>_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 <i>CYP2D6</i>, <i>SLC22A1</i> and <i>CYP3A4</i>. In addition to the previous associations, CYP2D6 UMs showed a lower AUC₇₂/DW (<i>p</i>_uv = 0.046, <i>p</i>_mv = 0.049, β = −68.80, R² = 0.073) compared to NMs, IMs and PMs and the <i>SLC22A1</i> rs34059508 G/A genotype was associated with thoracic pain (<i>p</i>_uv = 0.038) and dizziness (<i>p</i>_uv = 0.038, <i>p</i>_mv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and <i>CYP2D6</i> and <i>SLC22A1</i>. Further research is needed to gather more evidence before its application in clinical practice.