Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles

Review Article

Austin J Pharmacol Ther. 2016; 4(2).1085.

Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles

Ayano G*

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

Abstract

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

Introduction

Cytochromes P450 (CYPs) is microsomal monooxygenase family of enzymes, which oxidize drugs in the liver [1]. 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].

Psychotropic Medications Metabolized by CYPA2

Antipsychotic medications metabolized by CYP1A2

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].

Antidepressant medications etabolized by CYP1A2

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 [16].

Mood stabilizer medications metabolized CYP1A2

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.

Table 1: Main Psychotropic medications metabolized by CYP1A2.





  

    
Group    of drugs 

    
Drug    name 

  

  

    
Antidepressants    (tricyclics) 

    
Amitriptyline,    Clomipramine, Trimipramine, Imipramine, Doxepine 

  

  

    
Antidepressants    (SSRIs) 

    
Fluvoxamine 

  

  

    
Antidepressants    (others) 

    
Duloxetine,    Mirtazapine 

  

  

    
Antipsychotics    (first generations) 

    
Chlorpromazine,    Thioredazine, Haloperidol, Pepherazine, Pimozide, Stelazine 

  

  

    
Antipsychotics    (second generations) 

    
Clozapine,    Olanzapine 

  

  

    
Beta-blockers 

    
Propranolol,    Warfarin, Theophylline 

  









Table 1:  Main Psychotropic medications metabolized by CYP1A2.

Table 2: Summary cytochrome CYP1A2 substrates, inhibitors and inducers.





  

    
Substrate 

    
Inhibitors 

    
Inducers 

  

  

    
Olanzapine 

      
Pimozide 

      
Propranolol 

      
Ramelteon 

      
Rasagiline 

      
Riluzole 

      
Ropinirole 

      
Acetaminophen 

      
Amitriptyline 

      
Caffeine 

      
Chlordiazepoxide 

      
Clopidogrel 

      
Fluvoxamine 

      
Guanabenz 

      
Mirtazapine 

      
Desipramine 

      
Diazepam 

      
Estradiol 

      
Flutamide 

      
Haloperidol 

      
Imipramine 

      
levobupivacaine 

      
Warfarin 

      
Chlorprimazine 

    
Clozapine 

      
Cyclobenzaprine 

      
Doxepin 

      
Duloxetine 

      
Theophylline 

      
Trifluoperazine 

      
Alosetron 

      
Aminophylline 

      
Clomipramine 

      
(Estrogens:    conjugated 

      
and    estropipate estrone) 

      
Mexiletine 

      
Naproxen 

      
Nortriptyline 

      
Ondansetron 

      
Propafenone 

      
Riluzole 

      
Ropinirole 

      
Ropivacaine 

      
Tacrine 

      
Verapamil 

    
Caffeine 

      
Cimetidine 

      
Warfarin 

      
Verapamil 

      
Diltiazem 

      
Methoxsalen 

      
Mexiletine 

      
Nalidixic    acid 

      
Norethindrone 

      
Norfloxacin 

      
Ciprofloxacin 

      
Caffeine 

      
Theophylline 

      
Antipyrine 

      
Tacrolimus 

      
Grapefruit    juice 

    
Citalopram 

      
Clarithromycin 

      
Diltiazem 

      
Erythromycin 

      
Ethinyl    Estradiole 

      
Isoniazid 

      
Ketoconazole 

      
Oral-Contraceptives 

      
Paroxetine 

      
Tacrine 

      
Ticlopidine 

      
Troleandomycin 

      
Fluvoxamine 

      
Melatonon 

      
Fluoxetine 

      
Desipramine 

      
Miodarone 

    
Carbamazepine 

      
Primidone 

      
Rifampin 

      
Tobacco 

      
Omeperazole 

      
Insulin 

      
Barbiturates 

      
Cruciferous    Vegetables 

      
Grilled    meat 

  









Table 2:  Summary cytochrome CYP1A2 substrates, inhibitors and inducers.

Beta blockers metabolized by CYP1A2

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.

Drug Interactions Involving CYP1A2 Enzyme

SSRI and antipsychotic interactions

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].

Beta blockers and psychotropic’s

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].

Cigarette smoking and psychotropic’s

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 [40].

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].

References

  1. Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, et al. “The first virally encoded cytochrome P450”. Journal of Virology. 2009; 83: 8266-8269.
  2. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005; 352: 2211-2221.
  3. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother 1995; 29: 619-624.
  4. Sadock BJ, Sadock VA and Ruiz P. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th Edn. Philadelphia: Lippincott Williams & Wilkins, 2009.
  5. Spina E, deLeon J. Metabolic Drug Interactions with Newer Antipsychotics: A Comparative Review. Basic & Clinical Pharmacology & Toxicology. 2007; 100: 4-22.
  6. Roland Sigel, Sigel Astrid, Sigel Helmut. The Ubiquitous Roles of Cytochrome P450 Proteins: Metal Ions in Life Sciences. New York: Wiley. 2007.
  7. Freeman, MP, Wiegand, CB, Gelenberg, AJ. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edn. Schatzberg AF, Nemeroff CB, editors. American Psychiatric Publishing, Inc., 2009; 697.
  8. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd Edn. New York: Cambrigde University Press; 2008.
  9. Pan LP, Wijnant P, DeVriendt C, Rosseel MT and Belpaire FM. “Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol”. British Journal of Clinical Pharmacology. 1997; 557-564.
  10. Pirmohamed M, Williams D, Madden S, Templeton E, Park BK. Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther. 1995; 272: 984-990.
  11. Eiermann B, Engel G, Johansson I, Zanger UM, Bertilsson L. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol. 1997; 44: 439-446.
  12. Linnet K, Olesen OV. Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos. 1997; 25: 1379-1382.
  13. Olesen OV, Linnet K. Contributions of five human cytochrome P450 isoforms to the N- demethylation of clozapine in vitro at low and high concentrations. J Clin Pharmacol. 2001; 41: 823-832.
  14. Christensen M, Tybring G, Mihara K, Yasui-Furokori N, CarrilloJA, Ramos SI, et al. Low daily10-mg and 20-mg doses of fluvoxamine inhibit the metabolismof both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther. 2002; 71: 141-152.
  15. Spigset O, Axelsson S, Norstrom A, Hagg S, Dahlqvist R. The major fluvoxamine metabolite in urine is formed by CYP2D6. Eur J Clin Pharmacol. 2001; 57: 653-658.
  16. Sawada Y, Ohtani H. [Pharmacokinetics and drug interactions of antidepressive agents]. Nippon Rinsho. 2001; 59: 1539-1545.
  17. Madsen H, Nielsen KK, Brosen K. Imipramine metabolism inrelation to the sparteine and mephenytoin oxidation polymorphisms–a population study. Br J Clin Pharmacol. 1995; 39: 433-439.
  18. Maynard GL, Soni P. Thioridazine interferences with imipramine metabolism and measurement. Ther Drug Monit. 1996; 18: 729-731.
  19. Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, Gelboin HV. Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7- ethoxycoumarin,and imipramine metabolism. Drug Metab Dispos. 1999; 27: 102-109.
  20. Nielsen KK, Flinois JP, Beaune P, Brosen K. The biotransformation of clomipramine in vitro, identification of the cytochromeP450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther. 1996; 277: 1659- 1664.
  21. Olesen OV, Linnet K. Metabolism of the tricyclic antidepressantamitriptyline by cDNA- expressed human cytochrome P450 enzymes. Pharmacology. 1997; 55: 235-243.
  22. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI. Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP2C19 and 3A4. J Clin Pharmacol. 1998; 38: 112-121.
  23. Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine bioactivation in vitro I. characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos. 2002; 30: 1170-1179.
  24. Staines AG, Coughtrie MW, Burchell B. N-glucuronidation of carbamazepine in human tissues is mediated by UGT2B7. J Pharmacol Exp Ther. 2004; 311: 1131-1137.
  25. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet. 1996; 31: 198-214.
  26. Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Investig. 1993; 71: 1002-1009.
  27. Jeppessen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K. Dosedependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol. 1996; 51: 73- 78.
  28. Jeppesen U, Rasmussen BB, Brøsen K. Fluvoxamine inhibits the CYP2C19- catalyzed bioactivation of chloroguanide. Clin Pharmacol Ther. 1997; 62: 279-286.
  29. Chang WH, Augustin B, Lane HY, ZumBrunnen T, Liu HC, Kazmi Y, et al. Invitro and in-vivo evaluation of the drug–drug interaction between fluvoxamine and clozapine. Psychopharmacology. 1999; 145: 91-98.
  30. Olesen OV, Linnet K. Fluvoxamine-clozapine drug interaction inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism. J Clin Psychopharmacol. 2000; 20: 35-42.
  31. Weigmann H, Muller H, Dahmer W, Wetzel H, Hiemke C. Interaction of fluvoxamine with the metabolism of clozapine. Pharmacopsychiatry. 1993; 26: 209.
  32. Hiemke C, Weigmann H, Härtter S, Dahmen N, Wetzel H, Muller H. Elevated level of clozapine in serum after addition of fluvoxamine. J Clin Psychopharmacol. 1994; 14: 279-281.
  33. Jerling M, Lindström L, Bondesson U, Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit. 1994; 16: 368-374.
  34. Szegedi A, Weisner J, Hiemke C. Improved efficacy and fewer side effects under clozapine therapy after addition of fluvoxamine. J Clin Psychopharmacol. 1995; 15: 141-143.
  35. Dequardo JR, Roberts M. Elevated clozapine levels after fluvoxamine initiation. Am J Psychiatry. 1996; 153: 840-841.
  36. DuMartier G, Lochu A, Colon de Melo CP, Ghribi O, Roche-Rabreau D, DeGrassat K, et al. Elevated clozapine plasma concentrations after fluvoxamine initiation. Am J Psychiatry. 1996; 153: 738-739.
  37. Koponen HJ, Leinonen E, Lepola U. Fluvoxamine increases the serum clozapine levels significantly. Eur Neuropsychopharmacol. 1996; 6: 69-71.
  38. Armstrong SC, Stephans JR. Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage. J Clin Psychiatry. 1997; 58: 499.
  39. Heeringa M, Beurskens R, Schouten W, Verduijn MM. Elevated plasma levels of clozapine after concomitant use of fluvoxamine. Pharm World Sci. 1999; 21: 243-244.
  40. Swedish environmental classification of pharmaceuticals - FASS (drug catalog) - Facts for prescribers (Fakta för förskrivare).
  41. Janicak PG, Davis JM, Preskorn SH, Ayd FJ. Jr. Pharmacokinetics In: Principles and practice of psychopharmacotherapy. 3rd Edn. Baltimore (MD): Lippincott, Williams & Wilkins. 2001; 51-72.
  42. VanderWeide J, Steijns L, Van Weelden M. The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003; 13: 169-172.
  43. Meyer J. Individual Changes in Clozapine Levels After Smoking Cessation: Results and a Predictive Model. Journal of Clinical Pharmacology. 2001; 21: 569-574.
  44. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2000; 15: 469-494.
  45. Haring C, Meise U, Humpel C, Saria A, Fleischacker WW, Hinterhuber H. Dose- related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology (Berl) 1989; 99: 38-40.
  46. Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Hartter S, et al. Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol. 1998; 18: 2-9.
  47. Seppälä NH, Leinonen EVJ, Lehtonen ML, Kivistö KT. Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharmacol Toxicol. 1999; 85, 244-246.
  48. Desai HD, Seabolt J, Jann MW. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs. 2001; 15: 469-494.
  49. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007; 64: 1917-1921.

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.