Cytochrome antipsychotic metabolism

Shin, J.G., Soukhova, N. and Flockhart, D.A. (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro preferential inhibition of CYP2 D6. Drug Metabolism and Disposition, 27 (9), 1078-1084. 

Important biological differences that potentially affect the metabolism of psychotropics have been described between Japanese and non-Asian children. For example, a pharmacogenetic ethnic difference was reported in cytochrome P450 (CYP) 2D6 metabolism of several antipsychotics and antidepressants, and in the CYP 2C19 metabolism of tricyclic agents. In adults, the rate of poor metabolizers of CYP 2D6 substrates is lower in Asians (about 1%) than in Caucasians (about 7%), while that of CYP 2C19 substrates is higher in Asians (15%-30%) than in Caucasians (3%-6%) (Poolsup et ah, 2000). Clinicians may need to keep these differences in mind when they use psychotropics in Japanese and other Asian patients, since such differences can lead to different behavioral responses or toxicity. 

Fluoxetine and paroxetine inhibit cytochrome CYP P-450 2D6 and thus may affect metabolism of some opioids, e.g. codeine, 0) codone and tramadol, that are partly metabolised by CYP2D6, many antipsychotic drugs and tricyclic antidepressants. 

Urichuk L et al Metabolism of atypical antipsychotics Involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab 2008 9 410. [PMID 18537577]... 

Recall that one of the key drug-metabolizing enzymes is the cytochrome P450 (CYP450) enzyme called 1A2. Two atypical antipsychotic drugs are substrates of 1A2, namely olanzapine and clozapine. That means that when they are given con-... 

Potential interactions through the cytochrome P450 CYP 2D6 and CYP 3A4 enz)unes can be noted from Tables 19.2a and 19.2b. The combination of drugs that are substrates of the same enzyme creates potential for competitive inhibition of their metabolism with unexpected elevation of plasma concentration. Similarly, potent inhibitors, e.g. fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) and fluvoxamine (CYP 1A2), may cause adverse effects by reducing metabolic breakdown of co-prescribed drugs that are used in standard doses. Antidepressants are commonly prescribed with antipsychotics in a depressive... 

These differences in clinical response and pharmacokinetics have been attributed to ethnic differences in drug metabolism mediated through the cytochrome P450 microsomal enzyme system, which is responsible for the metabolism of most of the older psychotropic medications, including typical antipsychotics and TCAs (Lin et al. 1993 Silver et al. 1993). Earlier studies showed that Caucasians were more likely than Asians and African Americans to be poor metabolizers of psychotropic medication, a finding inconsistent with clinical experience, because poor metabolizers should require less medication. However, new mutations have recently been discovered in the enzymatic systems of the latter groups that are intermediate in the rate of metabolism. Thus, up to 47%-70% of African Americans and Asian Americans may be slow metabolizers, which could account for the higher incidence of side effects (Mendoza et al. 1999). 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

Movement disorders and raised antipsychotic serum levels seem most common with fluoxetine and paroxetine, possibly because they inhibit the metabolism of some antipsychotics by the cytochrome P450 isoenzyme CYP2D6. However, the movement disorders may just be a result of the additive adverse effects of antipsychotics and SSRIs. Fluoxetine alone has been shown to occasionally cause movement disorders. "... 

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