CYP2C19

Cytochroom P450 2C19 (afgekort CYP2C19) is een lid van de cytochroom P450 enzymfamilie. Het is een van de belangrijkste enzymen die lichaamsvreemde stoffen in het lichaam omzet. De lever bevat het meeste van dit enzym. Veel toegediende geneesmiddelen worden door dit enzym omgezet. Niet in iedere lever is CYP2C19 is gelijke mate aanwezig. Dit maakt dat een geneesmiddel niet bij iedereen op dezelfde manier effectief is. Met farmacogenetisch onderzoek kan worden achterhaald hoe en in welke mate bepaalde enzymen effect hebben.

Functie[bewerken | brontekst bewerken]

CYP2C19 is betrokken bij de synthese van lichaamseigen stoffen zoals steroïden en bij de omzetting van lichaamsvreemde stoffen, zoals gifstoffen en geneesmiddelen. Een geneesmiddel kan hierbij zowel onwerkzaam worden gemaakt of juist worden geactiveerd tot een werkzame stof.

Aangrijpingspunten[bewerken | brontekst bewerken]

Geneesmiddelen en andere stoffen die worden ingenomen kunnen op drie manieren te maken krijgen met CYP2C19:

als substraat - het wordt door het enzym omgezet in een andere stof (bijv. escitalopram);
als inhibitor/remmer - het remt de activiteit van het enzym (bijv. omeprazol);
als inducer/activator - het vergroot de activiteit van het enzym (bijv. prednison);

Verandering in activiteit kan leiden tot een groot verschil in werking van het toegediende middel, en daarmee tot grote verschillen in dosering.

inducers, inhibitors en substraten van CYP2C19
Substraat	Inhibitor	Inducer
antidepressiva TCAs amitriptyline^[1]^[2] clomipramine^[1]^[2] imipramine^[1]^[2] SSRIs (es)citalopram^[1]^[2] sertraline^[3] moclobemide^[1]^[2] bupropion^[4] anti-epileptica diazepam^[1]^[2] mefenytoine^[1]^[2] nordazepam^[2] fenytoïne^[2] (methyl)fenobarbital^[1] primidon^[1] hexobarbital^[1] protonpompremmers lansoprazol^[1]^[2] omeprazol^[1]^[2] pantoprazol^[1]^[2] rabeprazol^[1] esomeprazol^[2] clopidogrel^[1]^[2] (stolling), inactieve prodrug die pas werkzaam is na omzetting door een van de CYP2C19, CYP3A4, CYP2C9, CYP1A2, en CYP2B6 enzymen.^[5] proguanil^[1]^[2] (antimalaria) propranolol^[1]^[2] (bètablokker) limoneen^[6] (insecticide) gliclazide (antidiabeticum)^[7]^[8] carisoprodol^[1] (spierverslapper) chlooramfenicol^[1] (bacteriostaticum) cyclofosfamide^[1] (cytostaticum) indometacine^[1] (NSAID) nelfinavir^[1] (antiviraal) nilutamide^[1] (antiandrogeen) progesteron^[1] (hormoon) teniposide^[1] (chemotherapeuticum) warfarine^[1] (anticoagulans) tapentadol (analgeticum) voriconazol^[3] (antimycoticum) tamoxifen^[3] (SERM)	Sterk fluconazol^[9] (antimycoticum) ticlopidine^[9] (stolling) moclobemide^[2] (antidepressivum) fluvoxamine^[2] (SSRI) chlooramfenicol^[10] (bacteriostaticum fluoxetine^[11] (SSRI) Matig felbamaat^[9]^[12] (anti-epilepticum) Zwak topiramaat^[12] (migraine) omeprazol^[9] (protonpompremmer) voriconazol^[9] (antimycoticum) Onbekende sterkte protonpompremmers lansoprazol^[1] pantoprazol^[1] rabeprazol^[1] esomeprazol^[13] cimetidine^[1] (H2-receptorantagonist) indometacine^[1] (NSAID) ketoconazol^[1] (antimycoticum) modafinil^[1] (narcolepsie) probenecide^[1] (uricosuricum) isoniazide^[14] (antibioticum)	Onbekende sterkte rifampicine^[1]^[2] (bactericide) artemisinine^[2] (antimalaria) carbamazepine^[1] (anti-epilepticum) norethisteron^[1] (anticonceptie) prednison^[1] (corticosteroïden) aspirine in lage dosering (89 mg)^[15]

Bronnen, noten en/of referenties

↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table. Indiana University School of Medicine (2007). Geraadpleegd op 10 July 2011.
↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t (sv) Fakta för förskrivare: Interaktion mellan läkemedel. FASS Vårdpersonal. Geraadpleegd op 10 July 2011.
↑ ^a ^b ^c Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17
↑ Zhu AZ, Zhou Q, Cox LS, Ahluwalia JS, Benowitz NL, Tyndale RF (November 2014). Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes. Drug Metabolism and Disposition 42 (11): 1971–1977. PMID: 25187485. PMC: 4201132. DOI: 10.1124/dmd.114.060285.
↑ Alkattan A, Alsalameen E. "Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment". Expert Opin Drug Metab Toxicol. 2021 May 15:1–11. DOI:10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.
↑ Miyazawa M, Shindo M, Shimada T (May 2002). Metabolism of (+)- and (–)–limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metabolism and Disposition 30 (5): 602–607. PMID: 11950794. DOI: 10.1124/dmd.30.5.602.
↑ Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D (July 2007). Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. British Journal of Clinical Pharmacology 64 (1): 67–74. PMID: 17298483. PMC: 2000619. DOI: 10.1111/j.1365-2125.2007.02846.x.
↑ Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ (April 2008). Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. British Journal of Pharmacology 153 (7): 1579–1586. PMID: 18204476. PMC: 2437900. DOI: 10.1038/sj.bjp.0707685.
↑ ^a ^b ^c ^d ^e (26 May 2021). Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. FDA.
↑ Park JY, Kim KA, Kim SL (November 2003). Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes. Antimicrobial Agents and Chemotherapy 47 (11): 3464–3469. PMID: 14576103. PMC: 253795. DOI: 10.1128/AAC.47.11.3464-3469.2003.
↑ Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N (June 2014). Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clinical Pharmacology and Therapeutics 95 (6): 653–662. PMID: 24569517. PMC: 4029899. DOI: 10.1038/clpt.2014.50.
↑ ^a ^b Antiepileptic drugs, 5th. Lippincott Williams & Wilkins, Hagerstwon, MD (2002), "Combination Therapy and Drug Interactions", p. 100. ISBN 0781723213.
↑ Gjestad C, Westin AA, Skogvoll E, Spigset O (February 2015). Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline. Therapeutic Drug Monitoring 37 (1): 90–97. PMID: 24887634. PMC: 4297217. DOI: 10.1097/FTD.0000000000000101.
↑ Wen X, Wang JS, Neuvonen PJ, Backman JT (January 2002). Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes. European Journal of Clinical Pharmacology 57 (11): 799–804. PMID: 11868802. DOI: 10.1007/s00228-001-0396-3.
↑ Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH (March 2003). Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clinical Pharmacology and Therapeutics 73 (3): 264–271. PMID: 12621391. DOI: 10.1067/mcp.2003.14.

[Flockhart-1] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table. Indiana University School of Medicine (2007). Geraadpleegd op 10 July 2011.

[FASS-2] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t (sv) Fakta för förskrivare: Interaktion mellan läkemedel. FASS Vårdpersonal. Geraadpleegd op 10 July 2011.

[pmc2829691-3] Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17

[4] Zhu AZ, Zhou Q, Cox LS, Ahluwalia JS, Benowitz NL, Tyndale RF (November 2014). Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes. Drug Metabolism and Disposition 42 (11): 1971–1977. PMID: 25187485. PMC: 4201132. DOI: 10.1124/dmd.114.060285.

[5] Alkattan A, Alsalameen E. "Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment". Expert Opin Drug Metab Toxicol. 2021 May 15:1–11. DOI:10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.

[6] Miyazawa M, Shindo M, Shimada T (May 2002). Metabolism of (+)- and (–)–limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metabolism and Disposition 30 (5): 602–607. PMID: 11950794. DOI: 10.1124/dmd.30.5.602.

[pmid17298483-7] Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D (July 2007). Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. British Journal of Clinical Pharmacology 64 (1): 67–74. PMID: 17298483. PMC: 2000619. DOI: 10.1111/j.1365-2125.2007.02846.x.

[pmid18204476-8] Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ (April 2008). Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. British Journal of Pharmacology 153 (7): 1579–1586. PMID: 18204476. PMC: 2437900. DOI: 10.1038/sj.bjp.0707685.

[FDA_drug_development-9] (26 May 2021). Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. FDA.

[10] Park JY, Kim KA, Kim SL (November 2003). Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes. Antimicrobial Agents and Chemotherapy 47 (11): 3464–3469. PMID: 14576103. PMC: 253795. DOI: 10.1128/AAC.47.11.3464-3469.2003.

[11] Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N (June 2014). Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4. Clinical Pharmacology and Therapeutics 95 (6): 653–662. PMID: 24569517. PMC: 4029899. DOI: 10.1038/clpt.2014.50.

[Rene-12] Antiepileptic drugs, 5th. Lippincott Williams & Wilkins, Hagerstwon, MD (2002), "Combination Therapy and Drug Interactions", p. 100. ISBN 0781723213.

[ppis-13] Gjestad C, Westin AA, Skogvoll E, Spigset O (February 2015). Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline. Therapeutic Drug Monitoring 37 (1): 90–97. PMID: 24887634. PMC: 4297217. DOI: 10.1097/FTD.0000000000000101.

[14] Wen X, Wang JS, Neuvonen PJ, Backman JT (January 2002). Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes. European Journal of Clinical Pharmacology 57 (11): 799–804. PMID: 11868802. DOI: 10.1007/s00228-001-0396-3.

[pmid12621391-15] Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH (March 2003). Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clinical Pharmacology and Therapeutics 73 (3): 264–271. PMID: 12621391. DOI: 10.1067/mcp.2003.14.

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