Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients

Abstract

Abstract. The aim of the present study was to explore the effects of common genetic polymorphisms of cytochrome P450 (CYP)3A4, CYP3A5, cytochrome P450 oxidoreductase (POR) and multidrug resistance protein 1 (MDR1) on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients. The mild-to-moderate essential hypertension patients were recruited to complete the genotyping of CYP3A4, CYP3A5, POR and MDR1 by sequencing. After a 1-week placebo washout period, the subjects received 5 mg oral amlodipine daily for 4 weeks. Serial blood samples were collected prior to the last dosing, and 2, 6 and 24 h post-dosing. Blood pressures were measured prior and subsequent to dosing, and the demographical data were also collected. The blood samples were collected for laboratory testing. The plasma concentrations of amlodipine were determined by high-performance liquid chromatography/tandem mass spectrometry. A total of 60 patients, including 31 males and 29 females, completed the 4-week treatment. The plasma concentration of amlodipine in females at each time point was significantly higher compared to males (P<0.05). However, no significant gender differences existed in antihypertensive efficacy. The genetic polymorphisms of MDR1 C3435T had a certain impact on the plasma concentration of amlodipine, but did not affect its antihypertensive efficacy (P>0.05). The genetic polymorphisms of CYP3A4*1G, CYP3A5*3 and POR A503V showed no impact on plasma concentration and efficacy of amlodipine (P>0.05). Gender and MDR1 gene polymorphism may affect the plasma concentration of amlodipine in hypertensive patients. However, there was no impact on the efficacy of amlodipine.

Construction and verification of CYP3A5 gene polymorphisms using a Saccharomyces cerevisiae expression system to predict drug metabolism

“…DNA was extracted from patient peripheral blood samples prior to the treatment. Genotypes for the CYP3A5 polymorphisms were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism as previously described (13). Blood drug concentrations of each CYP3A5 genotype group was measured with liquid chromatography-mass spectrometry (LC-MS) (14,15) and high performance liquid chromatography (HPLC) (16).…”

Amlodipine drug therapeutic failure: a rare case report

“…9 However study by Chengxian et al reveals that genetic polymorphism of MDR1 ( multidrug resistance protein 1) C3435T and gender had a certain effect on plasma concentration of amlodipine but did not affect its antihypertensive efficacy thus genetic polymorphism of MDR1 had an effect on amlodipine pharmacokinetics but there was no influence on amlodipine pharmacodynamics. 10 High Salt intake exacerbates BP elevation during the development of hypertension in SHR (Spontaneously Hypertensive Rats) by activation of the sympathetic nervous system via an increase in ROS (reactive oxygen species) generation, probably due to activation of the AT1R/NAD (P) H oxidase pathways. 11 It is being hypothesized that changes in humoral or immunological factors may lead to systemic vasoconstriction and increase in vascular resistance which leads to elevation in blood pressure.…”

Allele-specific polymerase chain reaction for the detection of single nucleotide polymorphism in amlodipine-induced gingival enlargement

“…This polymorphism basically affects the expression and function of P‐gp, thereby potentially altering the pharmacokinetics of the drug. The pharmacodynamics and the efficacy of the drug however remain unaltered . This increase in concentration of the drug could also play an important role in causing complications like gingival enlargement.…”