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Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous DA‐8159, a new erectogenic, in rats
Author(s) -
Kim Yu C.,
Shim Hyun J.,
Lee Joo H.,
Kim Soon H.,
Kwon Jong W.,
Kim Won B.,
Lee Myung G.
Publication year - 2005
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.453
Subject(s) - chemistry , phenobarbital , pharmacology , pharmacokinetics , dexamethasone , enzyme inducer , inducer , cytochrome p450 , microsome , enzyme inhibitor , enzyme , endocrinology , biochemistry , medicine , gene
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 µg min/ml) and DA‐8164 (98.0 versus 79.8 µg 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 µg min/ml) and DA‐8164 (34.8 versus 76.5 µg 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. Copyright © 2005 John Wiley & Sons, Ltd.