Physiological disposition of changrolin
Abstract
Changrolin, 4-{3’,5’-bis[(N-pyrrolidinyl)methyl]-4’-hydroxyanilino}-quinazoline, is a new antiarrhythmic drug. This paper reports its physiological disposition.
Changrolin 125 mg/kg was injected im into rats. The excretion rates in 2 d were 12.0+/-(SD) 2.6% for feces, and 29.7+/-2.6% for urine. The urinary excretion rate of rabbits after im was about 22%. Peak plasma drug level were 19 and 27 microg/ml, respectively in 2 dogs at 15 min after im. The absorption after im was nearly complete, based on AUC value. Distribution studies were conducted on mice with [14C]changrolin. The radioactivity was highest in liver and alimentary tract, moderate in lungs and kidneys, slight in heart and spleen, and very low in brain.
The effects of different routes of administration on the plasma drug levels were studied on rats with [14C]changrolin. After an iv bolus, the plasma radioactivity declined as rapidly as that in dogs. Following im the radioactivity rose quickly and reached the maximum in c 5 min. Subsequent to an intragastric gavage the radioactivity attained a peak between 1.5 and 4 h. The bioavailabilities were 78% after im and 64% after ig medication.
A preliminary pharmacokinetic study was made on the postinfusion plasma level of dog C. The concentration-time curve may be adequately fitted by an open two-compartment model. A1=23.0, A2=3.04, K1=10.2, K2=0.22, t1/2alpha=4.1 min, t1/2beta=3.2 h, k10=1.62, k12=7.41, k21=1.39 h(-1), V1=0.77 l/kg, Vd=5.66 l/kg, clearance rate=20.7 ml/min. The biological t1/2=6.2 h for dog B, 3.2 h for dog C, 5.4 h for rabbit B, and c 11 h for mice.
Keywords:
Changrolin 125 mg/kg was injected im into rats. The excretion rates in 2 d were 12.0+/-(SD) 2.6% for feces, and 29.7+/-2.6% for urine. The urinary excretion rate of rabbits after im was about 22%. Peak plasma drug level were 19 and 27 microg/ml, respectively in 2 dogs at 15 min after im. The absorption after im was nearly complete, based on AUC value. Distribution studies were conducted on mice with [14C]changrolin. The radioactivity was highest in liver and alimentary tract, moderate in lungs and kidneys, slight in heart and spleen, and very low in brain.
The effects of different routes of administration on the plasma drug levels were studied on rats with [14C]changrolin. After an iv bolus, the plasma radioactivity declined as rapidly as that in dogs. Following im the radioactivity rose quickly and reached the maximum in c 5 min. Subsequent to an intragastric gavage the radioactivity attained a peak between 1.5 and 4 h. The bioavailabilities were 78% after im and 64% after ig medication.
A preliminary pharmacokinetic study was made on the postinfusion plasma level of dog C. The concentration-time curve may be adequately fitted by an open two-compartment model. A1=23.0, A2=3.04, K1=10.2, K2=0.22, t1/2alpha=4.1 min, t1/2beta=3.2 h, k10=1.62, k12=7.41, k21=1.39 h(-1), V1=0.77 l/kg, Vd=5.66 l/kg, clearance rate=20.7 ml/min. The biological t1/2=6.2 h for dog B, 3.2 h for dog C, 5.4 h for rabbit B, and c 11 h for mice.