Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous DA-8159, a new erectogenic, in rats.
In order to find what types of hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of DA-8159 and in the formation of DA-8164 in rats, enzyme inducers, such as dexamethasone, phenobarbital, 3-methylcholanthrene and isoniazid, and enzyme inhibitors, such as troleandomycin and quinine, were pretreated in rats. After a 1 min intravenous administration of DA-8159 at a dose of 30 mg/kg to rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the total areas under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8159 (283 versus 349 microg min/ml) and DA-8164 (98.0 versus 79.8 microg min/ml) were significantly smaller and greater, respectively, than those in control rats. However, the AUC values of DA-8159 were not significantly different after pretreatment with phenobarbital, isoniazid and 3-methylcholanthrene (main inducers of CYP2B1/2, 2E1 and 1A1/2, respectively, in rats). In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC values of DA-8159 (435 versus 370 microg min/ml) and DA-8164 (34.8 versus 76.5 microg min/ml) were significantly greater and smaller, respectively. However, in rats pretreated with quinine (a main inhibitor of CYP2D1 in rats), the AUC of DA-8159 was comparable to that in control rats. The above data indicate that DA-8159 was metabolized and DA-8164 was formed mainly via CYP3A1/2 in rats.
Kim
Yu C
YC
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Kwanak-Gu, Seoul, Republic of Korea.
Shim
Hyun J
HJ
Lee
Joo H
JH
Kim
Soon H
SH
Kwon
Jong W
JW
Kim
Won B
WB
Lee
Myung G
MG
D000429:Alcohol Oxidoreductases / Q000502:physiology; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D000429:Alcohol Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C504568:Cyp2d1 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides