Pharmacokinetic and pharmacodynamic consequences of inhibition of terazosin metabolism via CYP3A1 and/or 3A2 by DA-8159, an erectogenic, in rats.
OBJECTIVE
Recently, orthostatic hypotension was observed in patients with benign prostatic hyperplasia who are taking vardenafil (a PDE 5 inhibitor) and terazosin (a long acting alpha blocker). Therefore, this study was performed with DA-8159 (a long acting PDE 5 inhibitor) and terazosin in rats to find whether or not pharmacokinetic and pharmacodynamic interactions between the two drugs were observed.


METHODS
Pharmacokinetic and pharmacodynamic (changes in blood pressure) interactions between DA-8159 and terazosin were evaluated after simultaneous i.v. and p.o. administration of DA-8159 (30 mg kg(-1)) and terazosin (5 mg kg(-1)) to male Sprague-Dawley rats.


RESULTS
After simultaneous i.v. and p.o. administration of terazosin and DA-8159, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of terazosin became significantly greater (57.4 and 75.4% increase for i.v. and p.o. administration, respectively) than those of without DA-8159. The blood pressure dropping effect was considerable after simultaneous p.o. administration of DA-8159 and terazosin compared with each drug alone.


CONCLUSIONS
The significantly greater AUC of terazosin after both simultaneous i.v. and p.o. administration of both drugs could be due to the hepatic (both i.v. and p.o.) and intestinal (p.o.) inhibition of the metabolism of terazosin via CYP3A1 and/or 3A2 by DA-8159, since both DA-8159 and terazosin are metabolized via CYP3A1 and/or 3A2 in rats. The blood pressure lowering effect after simultaneous p.o. administration of both drugs could be due to significant increase in plasma concentrations of terazosin.
Oh
E Y
EY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Kwanak-Gu, Seoul, South Korea.
Bae
S K
SK
Kwon
J W
JW
You
M
M
Lee
D C
DC
Lee
M G
MG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008862:Microsomes, Liver / Q000378:metabolism; D011224:Prazosin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D014217:Troleandomycin / Q000494:pharmacology; D000096926:Benzenesulfonamides
D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone; D008565:Membrane Proteins; D011224:Prazosin; D011743:Pyrimidines; D013449:Sulfonamides; D014217:Troleandomycin; C502127:DA-8164; C041226:Terazosin; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides