Austin J Pharmacol Ther. 2016; 4(2).1085.
Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles
Research and Training Department, Amanuel Mental Specialized Hospital, Ethiopia
*Corresponding author: Getinet Ayano, Chief psychiatry professional and mhGap coordinator at Research and Training Department, Amanuel Mental Specialized Hospital, Addis Ababa, Ethiopia
Received: June 18, 2016; Accepted: September 23, 2016; Published: September 29, 2016
Psychotropic medications metabolized by cytochromes P450 (CYP) 1A2 is reviewed, and the possible relevance of this metabolism to drug-drug interactions is discussed. CYP1A2 is a member of the cytochrome P450 super family, is one of the best characterized. It is responsible for the metabolism of commonly drugs belonging to classes such as antidepressants, antipsychotics, mood stabilizers, beta blockers and Sedative/hypnotics. Fluvoxamine, amitriptyline, clomipramine, trimipramine, imipramine and doxepin are common antidepressants primarily metabolized by CYPA1A2 enzymes. First generation antipsychotics such as chlorpromazine, thioredazine haloperidol, pimozide, stelazine and pepherazine are primarily metabolized by CYP1A2 enzyme. Clozapine and Olanzapine are groups of second generation antipsychotics primarily metabolized by CYPA1A2. Propranolol, warfarin and theophylline are among the common beta blockers which are primarily metabolized by CYP1A2.
Drugs that inhibit CYP1A2 will predictably increase the plasma concentrations of the medications or decrease in clearance of substrates. Drugs such as ciprofloxacin, fluvoxamine, verapamil cimetdine , caffeine and isonaizid are inhibiters of CYP1A2 enzyme. Vegetables such as grape fruit juice, cumic and tumeric are inhibitors of the CYP1A2 enzyme which may leads to increase plasma concentration of psychotrohics.
Inducers of CYP1A2 enzyme such as Rifampin, Omeperazole, Insulin, Barbiturates omeperazole and carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents
Keywords: Cytochromes P450 (CYP) 1A2, Antipsychotics, Tricyclic antidepressants, Selective serotonin reuptake inhibitors, Beta blockers, Nicotine
Cytochromes P450 (CYPs) is microsomal monooxygenase family of enzymes, which oxidize drugs in the liver . These enzymes are haem-containing membrane proteins that are bound to the smooth endoplasmic reticulum of the hepatocytes. Metabolize the widest range of drugs [2,3].
There are more than 50 CYP450 enzymes. CYP1A2 is a member of the cytochrome P450 super family, is one of the best characterized. It is responsible for the metabolism of commonly drugs belonging to classes such as antidepressants, antipsychotics, mood stabilizers, beta blockers and Sedative/hypnotics [2,4].
CYP1A2 is involved in the metabolism of both first and second generation antipsychotics. First generation antipsychotics such as chlorpromazine, thioredazine haloperidol, pimozide, stelazine and pepherazine are primarily metabolized by CYP1A2 enzyme. Clozapine and Olanzapine are groups of second generation antipsychotics primarily metabolized by CYPA1A2 [4-13].
Fluvoxamine is Selective serotonin Reuptake Inhibitor (SSRI) which is primarily metabolized by CYPA1A2 enzymes and is a potent inhibitor of CYP1A2 [14,15].
Tricyclic Antidepressant (TCAs,) including amitriptyline, clomipramine, trimipramine, imipramine and doxepin are mainly metabolized by CYPA1A2 enzymes [16-22].
Other Antidepressants such as Duloxetine and Mirtazapine are metabolized by CYP1A2. Duloxetine is moderate to potent inhibitor of CYP1A2 but Mirtazapine has no significant inhibitory or inductive capabilities .
Majority of mood stabilizers including valproate, lamotrigine and topiramate are not metabolized by CYPA12 [4,6, 7,8]. Regarding carbamaepine, it is primarily metabolized by P450 3A4, although CYP1A2 metabolism serve as minor pathways and it induces CYP1A2 enzyme actions [23-25].
Lithium is mood stabilizers which is purely renally excreted, with no hepatic metabolic component. It lacks any inhibitory or inductive capabilities.
Group of drugs
Amitriptyline, Clomipramine, Trimipramine, Imipramine, Doxepine
Antipsychotics (first generations)
Chlorpromazine, Thioredazine, Haloperidol, Pepherazine, Pimozide, Stelazine
Antipsychotics (second generations)
Propranolol, Warfarin, Theophylline
Table 1: Main Psychotropic medications metabolized by CYP1A2.
and estropipate estrone)
Table 2: Summary cytochrome CYP1A2 substrates, inhibitors and inducers.
CYPA2 is also involved in metabolism of beta blockers. Propranolol, warfarin and theophylline are among the common beta blockers which are primarily metabolized by CYP1A2.
Coadmintration of fluvoxamine with second generation antipsychotics will increase their blood concentrations. Administration Fluvoxamine, a Selective Serotonin Reuptake Inhibitor (SSRI), a potent inhibitor of CYP 1A2, will elevate clozapine concentrations with potential for seizures and hypotension. Fluvoxamine also can cause increases in olanzapine levels. Concurrent use of clozapine with fluvoxamine could reduce the clearance of clozapine by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to three fold increase in the risk of the patient suffering a seizure [26-39].
Propranolol, warfarin and theophylline are among the common beta blockers which are primarily metabolized by CYP1A2, so that coadministration of drugs and other substance metabolized by cytochrome CYP1A2 affects the concentration of this drugs. Beta blockers such as Warfarin and theophylline are potent inhibitors of the hepatic enzyme CYP1A2, can produce toxicity in combination psychotrophic medication metabolized by CYP1A2, results in elevated plasma levels of other CYP1A2 substrates including antidepressant and antipsychotics [4,40,41].
Cytochrome P450 (CYP) 1A2 enzymes metabolise several clinically important drugs such as antidepressants and antipsychotics and a number of procarcinogens (such as those in cigarettes) Cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2 (via chemicals in cigarette smoke such as polycyclic aromatic hydrocarbons). cytochrome CYP1A2 is the only isoenzyme affected by tobacco. Cigarette smoking may lead to three fold increase in1A2 activity, which explains why smokers require higher doses of beta blockers than than non- smokers. Cigarette smoking induces dugs metabolized by CYP1A2 such as antidepressants (amitriptyline, duloxetine, fluvoxamine, imipramine), antipsychotics (clozapine, haloperidol olanzapine) and beta blockers (propranolol, theophylline and warfarin) [42-49]. Smoking as a potent inducer of CYP1A2, results in smokers having significantly reduced plasma concentrations of clozapine (up to 50%) and olanzapine compared to non-smokers. Some constituents of tobacco smoke are potent inducers of CYP1A2, but nicotine replacement therapy products do not produce the same effects due to he effect of smoking on hepatic enzymes is not related to the nicotine component of tobacco. When patients taking clozapine have ceased smoking, clozapine levels in clinical trials have risen 13- 260% which increase risks of side effects especially seizure [42,43]. Serum concentrations antidepressants, such as fluvoxamine may increase to toxic levels and result in adverse effects when a person quits smoking cigarette [48,49].
Common Medications, Nutrients and Substances Metabolized by Cytochrome CYP1A2, Inhibitors and Inducers of CYP1A2
Drugs metabolized by CYP1A2 are called CYP1A2 substrates. A number of other drugs which are metabolized by CYP1A2 may inhibit or induce the action of the enzyme. Drugs that inhibit CYP1A2 will predictably increase the plasma concentrations of the medications or decrease in clearance of substrates. Drugs such as ciprofloxacin, fluvoxamine, verapamil cimetidine, caffeine and isonaizid are inhibiters of CYP1A2 enzyme [40,41]. Vegetables such as grape fruit juice, cumic and tumeric are inhibitors of the CYP1A2 enzyme which may leads increase plasma concentration of psychotrohics .
Inducers of CYP1A2 enzyme such as Rifampin, Omeperazole, Insulin, Barbiturates omeperazole and carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents. From psychoactive substance tobacco and vegetable chargrilled meat, cauliflower, broccoli and brussels sprouts increase the activity of the cytochromeP450 1A2 isozyme [40,41].
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Citation: Ayano G. Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles. Austin J Pharmacol Ther. 2016; 4(2).1085. ISSN: 2373-6208.