Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs.
In vivo cardiovascular effects and bioavailability of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel cardiotonic agent, were investigated. In anesthetized dogs, intravenous administration of SCH00013 (0.3-10 mg/kg) increased maximum rate of rise in left ventricular pressure (LVdP/dtmax) in a dose-dependent manner with no change in heart rate (HR) and, at the dose of 3 mg/kg or higher, at which the increase in LVdP/dtmax reached the maximum, it decreased blood pressure. In conscious dogs, oral administration of SCH00013 (1-10 mg/kg) also increased LVdP/dtmax dose-dependently with no change in HR. The increase in the plasma concentration of orally administered SCH00013 (3 mg/kg) was parallel to the increase in LVdP/dtmax. The areas under the plasma concentration versus time curve (AUC0-24 h) after oral and intravenous administration of SCH00013 (3 mg/kg) were essentially identical (15.3 +/- 2.0 micrograms.h/ml and 16.5 +/- 2.1 micrograms.h/ml, respectively). These results suggest that oral bioavailability of SCH00013 is notably high. In conclusion, the positive inotropic effect of SCH00013 with neither elevation of HR nor excessive hypotension, as well as the high oral bioavailability of this compound, may provide a beneficial pharmacological treatment of the patients with congestive heart failure.
Yoshimura
A
A
Research Laboratory, Zenyaku Kogyo Co. Ltd., Tokyo, Japan.
Koide
Y
Y
Yoshioka
K
K
Hino
M
M
Sugawara
H
H
Sakato
M
M
Endoh
M
M
D000284:Administration, Oral; D000758:Anesthesia; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D004095:Dihydropyridines; D011724:Pyridazines; C115124:Sch 00013