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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Kristyna KrasulovaPavel Anzenbacher

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 d...Continue Reading

References

Jun 1, 1992·Clinical Pharmacokinetics·J G Kelly, K O'Malley
Feb 1, 1988·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A P BeresfordD A Stopher
Feb 3, 1998·Journal of Chromatography. B, Biomedical Sciences and Applications·J LuksaS Milutinovic
Aug 4, 1999·Trends in Pharmacological Sciences·M Ingelman-SundbergR A McLellan
May 12, 2000·European Journal of Biochemistry·E AnzenbacherováR Lange
Jul 5, 2001·Cellular and Molecular Life Sciences : CMLS·P Anzenbacher, E Anzenbacherová
Jul 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Andrew WilliamsSteven A Wrighton
Mar 24, 2005·The Journal of Pharmacology and Experimental Therapeutics·Aleksandra GaletinJ Brian Houston
Aug 16, 2005·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Shinichiro NishioKyoichi Ohashi
Nov 22, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Brian W OgilvieAndrew Parkinson
Sep 7, 2006·Proceedings of the National Academy of Sciences of the United States of America·Marika Ekroos, Tove Sjögren
Feb 3, 2007·Expert Opinion on Drug Metabolism & Toxicology·Robert J RileyRichard Weaver
Jun 1, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David R JonesStephen D Hall
Nov 15, 2008·Journal of the American College of Cardiology·Jolanta M Siller-MatulaBernd Jilma
Mar 4, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·E S PerloffD M Stresser
Feb 13, 2010·Pharmacogenetics and Genomics·Derek Van BoovenRuss B Altman
Oct 15, 2011·Journal of Computational Chemistry·Kiumars ShahrokhThomas E Cheatham
Feb 14, 2012·Chemical Research in Toxicology·F Peter Guengerich
Mar 28, 2012·Transplantation·Wei ZhaoEvelyne Jacqz-Aigrain
Dec 5, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yanlin ZhuWeiqing Chen
Sep 5, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Kristyna KrasulovaPavel Anzenbacher
Sep 6, 2015·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Matt Shirley, Paul L McCormack
Apr 5, 2016·Dental Clinics of North America·Robert J Weinstock, Michael P Johnson

❮ Previous
Next ❯

Citations

Oct 27, 2018·Expert Review of Clinical Pharmacology·Fabio AngeliGianpaolo Reboldi
Jan 15, 2020·European Journal of Clinical Pharmacology·Camille AzamFlorent Puisset
Jul 30, 2020·Expert Opinion on Drug Metabolism & Toxicology·Alexandra L DegraeveLaure Elens
Jul 9, 2021·European Journal of Drug Metabolism and Pharmacokinetics·Sherif M ShoiebAyman O S El-Kadi

❮ Previous
Next ❯

Software Mentioned

SPSS
GraphPad Prism
GBVI
Molecular Operating Environment ( MOE )
Sigma Plot
Statistica
Prism
MOE

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.