Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450
“…Calcium channel blockers are a group of medications used in the treatment of hypertension. − Most of these medications are sold as racemic mixtures, although it has been proven that some of them have a more active enantiomer, such as ( S )-nitrendipine and ( S )-amlodipine . These enantiopure 1,4-dihydropyridines (DHPs) can be obtained by stereoselective synthesis, resolution of 1,4-DHP salts, or kinetic resolutions, among other methods. , These methods of preparation are either expensive or experimentally difficult. TAMOF-1 -packed columns were able to efficiently separate the two enantiomers of amlodipine (selectivity term α equal to 2.4; entry 2, Table ; for the chromatogram, see Figure ).…”
Section: Resultsmentioning
confidence: 99%
“…103 These enantiopure 1,4-dihydropyridines (DHPs) can be obtained by stereoselective synthesis, resolution of 1,4-DHP salts, or kinetic resolutions, among other methods. 104,105 These methods of preparation are either expensive or experimentally difficult. TAMOF-1-packed columns were able to efficiently separate the two enantiomers of amlodipine (selectivity term α equal to 2.4; entry 2, Table 4; for the chromatogram, see Figure 7).…”
Metal−organic frameworks (MOFs) have become promising materials for multiple applications due to their controlled dimensionality and tunable properties. The incorporation of chirality into their frameworks opens new strategies for chiral separation, a key technology in the pharmaceutical industry as each enantiomer of a racemic drug must be isolated. Here, we describe the use of a combination of computational modeling and experiments to demonstrate that high-performance liquid chromatography (HPLC) columns packed with TAMOF-1 as the chiral stationary phase are efficient, versatile, robust, and reusable with a wide array of mobile phases (polar and non-polar). As proof of concept, in this article, we report the resolution with TAMOF-1 HPLC columns of nine racemic mixtures with different molecular sizes, geometries, and functional groups. Initial in silico studies allowed us to predict plausible separations in chiral compounds from different families, including terpenes, calcium channel blockers, or P-stereogenic compounds. The experimental data confirmed the validity of the models and the robust performance of TAMOF-1 columns. The added value of in silico screening is an unprecedented achievement in chiral chromatography.
“…Calcium channel blockers are a group of medications used in the treatment of hypertension. − Most of these medications are sold as racemic mixtures, although it has been proven that some of them have a more active enantiomer, such as ( S )-nitrendipine and ( S )-amlodipine . These enantiopure 1,4-dihydropyridines (DHPs) can be obtained by stereoselective synthesis, resolution of 1,4-DHP salts, or kinetic resolutions, among other methods. , These methods of preparation are either expensive or experimentally difficult. TAMOF-1 -packed columns were able to efficiently separate the two enantiomers of amlodipine (selectivity term α equal to 2.4; entry 2, Table ; for the chromatogram, see Figure ).…”
Section: Resultsmentioning
confidence: 99%
“…103 These enantiopure 1,4-dihydropyridines (DHPs) can be obtained by stereoselective synthesis, resolution of 1,4-DHP salts, or kinetic resolutions, among other methods. 104,105 These methods of preparation are either expensive or experimentally difficult. TAMOF-1-packed columns were able to efficiently separate the two enantiomers of amlodipine (selectivity term α equal to 2.4; entry 2, Table 4; for the chromatogram, see Figure 7).…”
Metal−organic frameworks (MOFs) have become promising materials for multiple applications due to their controlled dimensionality and tunable properties. The incorporation of chirality into their frameworks opens new strategies for chiral separation, a key technology in the pharmaceutical industry as each enantiomer of a racemic drug must be isolated. Here, we describe the use of a combination of computational modeling and experiments to demonstrate that high-performance liquid chromatography (HPLC) columns packed with TAMOF-1 as the chiral stationary phase are efficient, versatile, robust, and reusable with a wide array of mobile phases (polar and non-polar). As proof of concept, in this article, we report the resolution with TAMOF-1 HPLC columns of nine racemic mixtures with different molecular sizes, geometries, and functional groups. Initial in silico studies allowed us to predict plausible separations in chiral compounds from different families, including terpenes, calcium channel blockers, or P-stereogenic compounds. The experimental data confirmed the validity of the models and the robust performance of TAMOF-1 columns. The added value of in silico screening is an unprecedented achievement in chiral chromatography.
“…Therefore, the impact of non-genetic factors (medication, chronic alcohol consumption) on CYP2B6-selective S -mephenytoin N -demethylase activity was also investigated. The CYP2B6 inducers (dexamethasone, methylprednisolone, prednisolone, hydrocortisone, cortisone, midazolam, felodipine, diazepam) and the CYP2B6-selective inhibitor amlodipine as well as non-specific non-genetic factors (amoxicillin + clavulanic acid therapy, alcohol consumption) that can increase or decrease CYP2B6 expression and/or function were assumed to result in modification of the genetically determined CYP2B6 activity (Table 3 ) 25 , 49 – 57 . Figure 3 Hepatic CYP2B6 activity ( S -mephenytoin N -demethylation) ( A ) and CYP2B6 expression ( B ) in subjects belonging to various CYP2B6 genotype groups.…”
Section: Resultsmentioning
confidence: 99%
“…In two subjects, one with CYP2B6*1/*1 , the other with CYP2B6*5/*6 genotype, and predicted to be ‘normal’ and ‘intermediate’ metabolizers, respectively, the low S- mephenytoin N -demethylation was attributed to the antihypertensive amlodipine therapy that might have transiently evoked poor CYP2B6 activity. Furthermore, the exposure to CYP2B6 inducers, including the antibiotics rifampicin, the corticosteroid derivative prednisolone, cortisone, hydrocortisone and dexamethasone, the benzodiazepine diazepam and midazolam, and the calcium channel blocker felodipine induces transcriptional expression of CYP2B6 gene via nuclear receptors (PXR, CAR) 25 , 50 , 52 , 53 , 55 , 57 , 71 . Rifampicin treatment has been demonstrated to substantially increase the clearance of bupropion and the formation of hydroxy-bupropion metabolite 72 .…”
Human CYP2B6 enzyme although constitutes relatively low proportion (1–4%) of hepatic cytochrome P450 content, it is the major catalyst of metabolism of several clinically important drugs (efavirenz, cyclophosphamide, bupropion, methadone). High interindividual variability in CYP2B6 function, contributing to impaired drug-response and/or adverse reactions, is partly elucidated by genetic polymorphisms, whereas non-genetic factors can significantly modify the CYP2B6 phenotype. The influence of genetic and phenoconverting non-genetic factors on CYP2B6-selective activity and CYP2B6 expression was investigated in liver tissues from Caucasian subjects (N = 119). Strong association was observed between hepatic S-mephenytoin N-demethylase activity and CYP2B6 mRNA expression (P < 0.0001). In less than one third of the tissue donors, the CYP2B6 phenotype characterized by S-mephenytoin N-demethylase activity and/or CYP2B6 expression was concordant with CYP2B6 genotype, whereas in more than 35% of the subjects, an altered CYP2B6 phenotype was attributed to phenoconverting non-genetic factors (to CYP2B6-specific inhibitors and inducers, non-specific amoxicillin + clavulanic acid treatment and chronic alcohol consumption, but not to the gender). Furthermore, CYP2B6 genotype–phenotype mismatch still existed in one third of tissue donors. In conclusion, identifying potential sources of CYP2B6 variability and considering both genetic variations and non-genetic factors is a pressing requirement for appropriate elucidation of CYP2B6 genotype–phenotype mismatch.
“…Evidence for stereoselective inhibition of CYPs by some other dihydropyridine calcium channel blockers has been presented recently. For example, (+)-benidipine and (+)-felodipine were reported to strongly inhibit CYP3A and CYP2C19, respectively [ 28 ]. This work demonstrates that both R - and S -amlodipine are effective reversible and time-dependent inhibitors of CYP3A enzyme activities in human liver microsomes.…”
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.
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