Pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidine-7-one (DA-8159) and nitroglycerin in rats.
The pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d)pyrimidine-7-one (DA-8159), a new erectogenic, and nitroglycerin has been evaluated in rats. Male Sprague-Dawley rats received DA-8159 (30 mg kg(-1)) as a single intravenous or oral dose with the simultaneous single intravenous administration of nitroglycerin (2.5 mg kg(-1)). After simultaneous intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUC(inf)) of DA-8159 (746 vs 457 microg min mL(-1)) was found to be significantly greater than with DA-8159 alone. Also, after simultaneous intravenous administration total body clearance (CL) (40.2 vs 65.6 mL min(-1) kg(-1)), renal clearance (CL(R)) (1.65 vs 5.11 mL min(-1) kg(-1)), and nonrenal clearance (CL(NR)) (38.3 vs 60.2 mL min(-1) kg(-1)) of DA-8159 were significantly slower compared with DA-8159 alone. The slower CL(NR) of DA-8159 could have been due to the inhibition of the metabolism of DA-8159 by nitroglycerin, since DA-8159 is metabolized via CYP3A1/2 in rats and nitroglycerin inhibits CYP3A1/2 in rats. The slower CL(R) of DA-8159 could have been due to the urine flow rate-dependent CL(R) of DA-8159 in rats. After the simultaneous intravenous administration of nitroglycerin and DA-8159, the AUC(inf) of nitroglycerin was significantly smaller (635 vs 960 microg min mL(-1)), which could have been due to the cardiac output-dependent CL of nitroglycerin. However, after the oral administration of DA-8159, the pharmacokinetic parameters of DA-8159 with and without the intravenous administration of nitroglycerin became comparable. This was not due to the decrease in nitroglycerin's gastrointestinal absorption of DA-8159, but could have been due to changes in nitroglycerin's intestinal firstpass effect of DA-8159. Human studies are required to determine the administration time of DA-8159 when nitroglycerin is concomitantly taken.
Lee
Shin Jung
SJ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
Bae
Soo Kyung
SK
Kwon
Jong Won
JW
You
Moohi
M
Lee
Duk Chul
DC
Lee
Myung Gull
MG
D000818:Animals; D004338:Drug Combinations; D004347:Drug Interactions; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000096926:Benzenesulfonamides
D004338:Drug Combinations; D005996:Nitroglycerin; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014665:Vasodilator Agents; C502127:DA-8164; C419664:udenafil; D000096926:Benzenesulfonamides