Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, tadalafil, and vardenafil.
Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.
Dustan Sarazan
R
R
Lilly Research Laboratories, Eli Lilly and Company, 2001 W. Main St., Greenfield, Indianapolis, IN 46140, USA. sarazan@lilly.com
Crumb
William J
WJ
Beasley
Charles M
CM
Emmick
Jeffrey T
JT
Ferguson
Kenneth M
KM
Strnat
Christine A
CA
Sausen
Peter J
PJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002243:Carbolines / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000201:enzymology / Q000503:physiopathology; D000068581:Tadalafil; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014693:Ventricular Fibrillation / Q000201:enzymology / Q000503:physiopathology
D002243:Carbolines; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C092509:KCNH6 protein, human; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D024642:Potassium Channels, Voltage-Gated; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human