Contribution of Human Hepatic Cytochrome P450 Isoforms to the Metabolism of Psychotropic Drugs

Abstract

The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that V max /K m values in human liver microsomes were the highest for tofisopam, followed by tandospironeϾclotiazepamϾimipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5 m mM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10 m mM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform(s) of older drugs, for which metabolic profiles have not been reported.

RETRACTED ARTICLE: Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes

“…6). Niwa et al, using only recombinant P450 isoforms (12), similarly reported that tandospirone was metabolized by CYP3A4, but in the present study we were able to demonstrate its primary involvement using human liver microsomes, and also could specifical1y indicate each primary pathway of tandospirone metabolism via CYP3A4 and CYP2D6 by determining the major metabolites in our inhibition study (Fig. 6).…”

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

“…5,15) Many of the psychotropic drugs, including fluoxetine (a selective serotonin reuptake inhibitor, SSRI), imipramine (a tricyclic antidepressant and a serotonin and noradrenaline reuptake inhibitor), and desipramine (a noradrenaline reuptake inhibitor), are metabolized by CYP2D and/or inhibit the CYP2D-mediated metabolic activities. 8,15,[19][20][21][22][23] One of the dopamine uptake sites in the brain displays high affinity for dopamine uptake inhibitors such as mazindol, a noradrenaline reuptake inhibitor. 24,25) The other site displays rather high affinity for piperizine derivatives and has been termed the piperazine acceptor site.…”

In Vitro Prediction and in Vivo Verification of Enantioselective Human Tofisopam Metabolite Profiles

“…Kinetic constants were determined for all of the enzymes that demonstrated the potential to metabolize tofisopam, CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP3A, plus CYP2C8, which was indicated in a previous study (Niwa et al, 2005) as being involved in the metabolism of racemic tofisopam. To ensure that the experimentally determined rates were conducted under initial rate conditions, the amount of recombinant P450 was reduced from 5 pmol to 2 pmol and the incubation time was decreased from 15 min to 5 min.…”

“…To our knowledge, this is the first report of stereoselective metabolism of tofisopam. A recent study using recombinant P450 evaluated the ability of individual isozymes to metabolize a number of psychotropic drugs, including racemic tofisopam (Niwa et al, 2005). The study followed tofisopam depletion; thus, no information was given about the metabolites generated.…”