Influence of Amlodipine Enantiomers on Human Microsomal Cytochromes P450: Stereoselective Time-Dependent Inhibition of CYP3A Enzyme Activity

Abstract

Amlodipine (AML) is available as a racemate, i.e., a mixture of R- and S-enantiomers. Its inhibitory potency towards nine cytochromes P450 (CYP) was studied to evaluate the drug–drug interactions between the enantiomers. Enzyme inhibition was evaluated using specific CYP substrates in human liver microsomes. With CYP3A, both enantiomers exhibited reversible and time-dependent inhibition. S-AML was a stronger reversible inhibitor of midazolam hydroxylation: the Ki values of S- and R-AML were 8.95 µM, 14.85 µM, respectively. Computational docking confirmed that the enantiomers interact differently with CYP3A: the binding free energy of S-AML in the active site was greater than that for R-AML (−7.6 vs. −6.7 kcal/mol). Conversely, R-AML exhibited more potent time-dependent inhibition of CYP3A activity (KI 8.22 µM, Kinact 0.065 min−1) than S-AML (KI 14.06 µM, Kinact 0.041 min−1). R-AML was also a significantly more potent inhibitor of CYP2C9 (Ki 12.11 µM/S-AML 21.45 µM) and CYP2C19 (Ki 5.97 µM/S-AML 7.22 μM. In conclusion, results indicate that clinical use of S-AML has an advantage not only because of greater pharmacological effect, but also because of fewer side effects and drug–drug interactions with cytochrome P450 substrates due to absence of R-AML.

Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects

“…Therefore, in addition to CYP2C9 genotype, the impact of CYP2C8*3 allele and non-genetic phenoconverting factors (sex, medication, alcohol consumption) on CYP2C9 activity was investigated 22 , 32 , 36 , 37 . The impact of CYP2C9 inducers (dexamethasone, methylprednisolone, midazolam) and CYP2C9 inhibitors (amlodipine, tamoxifen) as well as of non-specific non-genetic factors, such as chronic alcohol consumption and amoxicillin + clavulanic acid therapy that can increase transcriptional expression of CYP2C9 or decrease CYP2C9 enzyme activities 3 , 37 – 41 was taken into account in CYP2C9 phenotype prediction (Table 3 ). The cohort of tissue donors were divided into four groups according to their CYP2C9 genotypes ( CYP2C9*1/*1 , CYP2C9*1/*2 , CYP2C9*1/*3 and CYP2C9*2/*2 or CYP2C9*2/*3 ).…”

“…The racemic mixture of the anti-hypertensive amlodipine is used for therapeutic purposes; however, vasodilation is ascribed only to its S -enantiomer. Amlodipine has been reported to inhibit CYP2C9 activity in a stereoselective manner, and R -enantiomer was proved to be more potent CYP2C9 inhibitor than S -amlodipine 41 . The risk of drug interactions with CYP2C9 substrates has also been predicted during co-administration of the selective estrogen receptor modulator tamoxifen 60 .…”

Metabolic Drug Interactions with Immunosuppressants

“…The metabolism of all three Ca-channel blockers is primarily catalyzed by CYP3A4, anticipating potential drug interactions with immunosuppressants. Furthermore, significant inhibition of CYP3A4 by diltiazem, verapamil, and amlodipine has been demonstrated with an additional inhibitory property of metabolite intermediate complex formation that catalytically inactivates CYP3A4 and CYP3A5 enzymes [79,80,82,[110][111][112][113][114]. The inactivation of CYP3A enzymes by comedication with these antihypertensive drugs consequently leads to a permanent increase in blood concentrations of calcineurin inhibitors or mTOR inhibitors [115][116][117][118][119][120][121][122].…”

Investigation of the enantioselective interaction between selected drug enantiomers and human serum albumin by mobility shift‐affinity capillary electrophoresis

“…AML is a dihydropyridine CCB used as a treatment choice of hypertension and coronary artery disease [9,10]. The chemical structure of AML possesses an asymmetric carbon atom, resulting in the existence of R-(+)and S-(−)enantiomers.…”

“…However, both enantiomers do not possess the same potency as calcium channel inhibitors. The S ‐(−)‐enantiomer of AML shows the antihypertensive effect, which is approximately 1000 times stronger than the R ‐(+)‐enantiomer [10]. Therefore, the S ‐(−)‐form is considered to be most responsible as CCB‐mediated pharmacodynamics action [11].…”