Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry.
Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SPprodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RPprodugs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SPmetabolites ± amiodarone, but no D-ala,RPmetabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SPprodrug metabolite formation, yet exacerbated L-ala,SP+ amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SPprodrug-dependent in cardiomyocytes.
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Armando
A
Lagrutta
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Christopher P
CP
Regan
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Haoyu
H
Zeng
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
John P
JP
Imredy
Dept. Preclinical ADME, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MRL, Merck &Co., West Point, PA, USA.
Kenneth
K
Koeplinger
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Pierre
P
Morissette
Dept. Investigative Laboratory Sciences, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Liping
L
Liu
Dept. Pathology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Gordon
G
Wollenberg
Dept. Program Development, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Christopher
C
Brynczka
Dept. Investigative Laboratory Sciences, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
José
J
Lebrón
Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Joseph
J
DeGeorge
Dept. Safety and Exploratory Pharmacology, Safety Assessment and Laboratory Animal Resources, MRL, Merck &Co., West Point, PA, USA.
Frederick
F
Sannajust
D000638:Amiodarone / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000998:Antiviral Agents; D020746:Calcium Channels, L-Type; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C419385:L-type calcium channel alpha(1C); C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase