Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety

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 (t1/2) (univariate p-value (puv) = 0.039, multivariate p-value (pmv) = 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) (puv = 0.025; pmv = 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 (puv = 0.046, pmv = 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 (puv = 0.038) and dizziness (puv = 0.038, pmv = 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.

Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide

“…However, no differences were found in exposure, probably because only 20% of valsartan is metabolized and only two CYP2D6 PMs were included in this research. CYP2D6 seem to participate in the metabolism of other antihypertensive drugs, such as diltiazem or amlodipine, as seen in our previous work derived from the same cohort of healthy volunteers [6]. Notwithstanding, its role on valsartan metabolism has not been described.…”

“…To our knowledge, no evidence of this association is available in the literature; however, hydrochlorothiazide was previously described as substrate of other transporters of the SLC22A family [27]. Additionally, OCT1 was found to be involved in amlodipine transport in a previous work derived from the same cohort of healthy volunteers [6]. Thus, this transporter might be especially relevant in antihypertensive treatment.…”

“…Of the 212 volunteers participating in the seven bioequivalence clinical trials (CTs), 64 (27 women and 37 men) gave written informed consent for the candidate gene study and had previously been genotyped in other research [6]. Women were older than men and presented a lower height, weight and body mass index (BMI) (p = 0.011, p < 0.001, p < 0.001, p = 0.029, respectively).…”

“…Since hydrochlorothiazide was present in all formulations but CT 1 (n = 6), pharmacokinetic data for this drug were available in 58 healthy volunteers; olmesartan data were available in 37 and valsartan in 26. Amlodipine pharmacokinetics and safety derived from these healthy volunteers were evaluated in an association study previously published [6]. The time-concentration curves for the three drugs included in this study are shown in Figure 1.…”

“…For CTs 5, 6, and 7, the wash out time was 21 days. All the formulations included a 10 mg amlodipine dose and its pharmacogenetic results are already published [6]. Although amlodipine is a widely-used and effective antihypertensive drug, the dose administered was the same in all formulations; therefore, it could be discarded as being responsible for the observed differences in efficacy and safety.…”