|show drug details|
|piperazine, 1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H- imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-, cis-|
|Piperazine, 1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-, cis-|
|show target details|
|Cytochrome P450 3A3|
|Cytochrome P450 3A4|
|PDB IDs:||1TQN 1W0E 1W0F 1W0G 2J0D 2V0M |
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo.. L L von Moltke; D J Greenblatt; S X Duan; J S Harmatz; C E Wright; R I Shader (1996) Journal of clinical psychopharmacology display abstract
Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons.
Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources.. S Rotzinger; J Fang; G B Baker (1998) Drug metabolism and disposition: the biological fate of chemicals display abstract
The metabolism of the antidepressant drug trazodone to its active metabolite, m-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomal preparations and cDNA-expressed human cytochrome P450 (P450) enzymes. The kinetics of mCPP formation from trazodone were determined, and three in vitro experiments were performed to identify the major P450 enzyme involved. Trazodone (100 microM) was incubated with 16 different human liver microsomal preparations characterized for activities of 7 different P450 isoforms. The production of mCPP correlated significantly with activity of cytochrome P4503A4 (CYP3A4) only. Trazodone (100 microM) was then incubated with microsomes from cells expressing human CYP1A1, CYP1A2, CYP2C8, CYP2C9arg, CYP2C9cys, CYP2C19, CYP2D6, or CYP3A4. Only incubations with CYP3A4 resulted in mCPP formation. In the third experiment, the CYP3A4 inhibitor ketoconazole was found to inhibit mCPP formation concentration dependently in both human liver microsomes and in microsomes from cells expressing human CYP3A4. The present results indicate that trazodone is a substrate for CYP3A4, that CYP3A4 is a major isoform involved in the production of mCPP from trazodone, and that there is the possibility of drug-drug interactions with trazodone and other substrates, inducers and/or inhibitors of CYP3A4.