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

Abstract

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.