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 mgkg−1) as a single intravenous or oral dose with the simultaneous single intravenous administration of nitroglycerin (2.5 mgkg−1). After simultaneous intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUCinf) of DA-8159 (746 vs 457 μg 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 (CLR) (1.65 vs 5.11 mL min−1 kg−1), and nonrenal clearance (CLNR) (38.3 vs 60.2 mL min−1 kg−1) of DA-8159 were significantly slower compared with DA-8159 alone. The slower CLNR 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 CLR of DA-8159 could have been due to the urine flow rate-dependent CLR of DA-8159 in rats. After the simultaneous intravenous administration of nitroglycerin and DA-8159, the AUCinf of nitroglycerin was significantly smaller (635 vs 960 μg 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 first-pass effect of DA-8159. Human studies are required to determine the administration time of DA-8159 when nitroglycerin is concomitantly taken.