Kutshanje, iBritish Journal of Clinical Pharmacology ipapashe isikhokelo sokuqala seklinikhi esaphuhliswa yi-UK Centre of Excellence for Regulatory Science and Innovation in Pharmacogenomics (CERSI PGx), esinesihloko esithi “Uvavanyo lwe-CYP2C19 genotype lwe-clopidogrel: Isikhokelo esaphuhliswa yi-UK Centre of Excellence yesayensi yokulawula kunye nokuvelisa izinto ezintsha kwi-pharmacogenomics (CERSI PGx)”. Olu xwebhu lubalulekileyo lugxile kwixabiso leklinikhi le-CYP2C19 genotyping kunyango lwe-clopidogrel olukhokelayo.
Malunga neCERSI PGx
I-CERSI PGx yenye yeziko ezisixhenxe zenzululwazi nophuhliso ezixhaswa ngurhulumente wase-UK ezaqaliswa ngoJanuwari 2025. Ikhokelwa yiYunivesithi yaseLiverpool, ixhaswa ngemali yi-Innovate UK, iBhunga loPhando lwezoNyango (i-MRC), i-Arhente yoLawulo lweeMveliso zamayeza kunye nezeMpilo (i-MHRA), kunye ne-Ofisi yeSayensi yoBomi (i-OLS). Eli ziko lijolise ekukhawuleziseni ukuhlanganiswa okukhuselekileyo nokusebenzayo kwe-pharmacogenomics (i-PGx) kwiNkonzo yezeMpilo yeSizwe (i-NHS) ngokujongana nemiqobo ephambili yokuphunyezwa. Esi sikhokelo siphawula isikhokelo sokuqala seklinikhi esikhutshwe ukusukela oko kwasekwa i-CERSI PGx.
Kutheni i-CYP2C19 ibalulekile kwiClopidogrel
I-CYP2C19 lilungu eliphambili losapho lwe-cytochrome P450 enzymes, elinoxanduva lokusebenza okanye ukungasebenzi kwe-metabolic yamayeza amaninzi. Ii-polymorphisms ze-genetic kwi-CYP2C19 zikhokelela kumahluko abalulekileyo phakathi komntu ngamnye kwi-metabolism yamayeza, nto leyo echaphazela ukusebenza kakuhle kunye nokhuseleko.
I-Clopidogrel sisixhobo esisetyenziswa kakhulu ekuthinteleni iziganeko ze-thrombotic kwisifo se-coronary artery, i-ischemic stroke, isifo se-peripheral artery, kunye ne-atrial fibrillation. Njenge-prodrug, i-clopidogrel ifuna ukusebenza kwe-metabolic yi-CYP2C19. Esi sikhokelo sihlula abantu kwi-ultrapid, rapid, normal, intermediate, kunye ne-malmal metabolisers ngokusekelwe kwi-CYP2C19 genotype. Abathwali bokulahlekelwa zii-alleles zomsebenzi (umz., i-CYP2C192 kunye ne-*3*) - ii-metaboliser eziphakathi kunye nezimbi - abanakuyenza isebenze i-clopidogrel ngokufanelekileyo, nto leyo ekhokelela ekuthintelweni kweeplatelet ngokwaneleyo kunye nomngcipheko ophezulu we-thrombosis ephindaphindayo.
I-allele ye-CYP2C192 ixhaphake malunga ne-15% kubantu baseYurophu, i-30% kubantu baseMzantsi Asia, kwaye ifikelela kwi-60% kubantu bomthonyama base-Ocean.
Ingcebiso Ephambili: Uvavanyo lwe-Clopidogrel lwe-Universal CYP2C19
Isikhokelo sithi, nokuba yintoni na eboniswayo, bonke abaguli abajongwayo kwi-clopidogrel kufuneka bathathe unyango.I-CYP2C19uhlalutyo lwe-genotyping.Ngokusekelwe kwiziphumo, unyango lwe-antiplatelet kufuneka luphuculwe:
-Ii-metaboliser ezingalungangaKufuneka bayiphephe i-clopidogrel kwaye bakhethe ukusebenzisa ezinye iziyobisi ezingaxhomekekanga kwi-metabolism ye-CYP2C19, njenge-ticagrelor okanye i-prasugrel.
-Ii-metabolizers eziphakathiKufuneka kuqwalaselwe nezinye iindlela zokwenza amayeza okanye iindlela ezihlengahlengisiweyo endaweni yokunyusa nje idosi ye-clopidogrel.
E-UK, i-clopidogrel ivunyiwe ukuthintela okwesibini iziganeko ze-atherothrombotic, kwi-intermediate risk transient ischemic attack (TIA) okanye i-mild ischemic stroke, kunye nokuthintela iziganeko ze-atherothrombotic kunye ne-thromboembolic kwi-atrial fibrillation.
Ngaphaya kweClopidogrel: Amanye Amayeza Apho i-CYP2C19 Genotyping Ibaluleke Kakhulu
Ixabiso le-CYP2C19 genotyping lidlula kude i-clopidogrel. Njenge-enzyme ephambili yokugutyula amayeza, i-CYP2C19 ikwadlala indima ebalulekileyo kwi-metabolism ye-voriconazole, amayeza okudakumba aliqela, kunye ne-proton pump inhibitors (PPIs). Izikhokelo ezininzi zamazwe ngamazwe nezesizwe zicebisa ukwenziwa kwe-genotype ekhokelwa yi-individualization kwezi ziyobisi.
1. Ii-Antidepressants (ii-SSRI)
Ii-selective serotonin reuptake inhibitors (SSRIs) – ezifana ne-sertraline, i-citalopram, kunye ne-escitalopram – zizinto zokuqala ezibangela ukudakumba kwaye zisetyenziswa kakhulu yi-CYP2C19. Umsebenzi we-enzyme ye-CYP2C19 umisela ngokuthe ngqo uxinzelelo lwe-plasma lwala mayeza. Ii-metaboliser ezingalunganga zinokunciphisa ukususwa kwamayeza nge-30%–60%, nto leyo ebangela ukuba zibe nemiphumo emibi efana nokwandiswa kwexesha le-QT kunye nokuthomalalisa. Ii-metaboliser ezikhawulezayo kakhulu zihlala zinezinga le-plasma elingaphantsi konyango, nto leyo ekhokelela ekuphendulweni konyango okulibazisekayo kunye nomngcipheko ophezulu wokuyeka ukusebenzisa amayeza.
Isikhokelo se-2023 Clinical Pharmacogenetics Implementation Consortium (CPIC) sithi abantu abasebenzisa i-citalopram okanye i-escitalopram kakubi banomngcipheko ophezulu wokwandiswa kwexesha le-QT kwaye bacebisa ukunciphisa idosi ngama-50%. Isikhokelo se-2021 Dutch Pharmacogenetics Working Group (DPWG) sicebisa ukuba abantu abasebenzisa i-metaboliser kakubi kufuneka bafumane idosi ephezulu ye-escitalopram encitshiswe ngama-50%, kwaye abantu abasebenzisa i-ultrapid metaboliser kufuneka bayiphephe ngokupheleleyo i-escitalopram. Kwi-sertraline, i-DPWG icebisa idosi yemihla ngemihla engadluli kwi-75 mg kubantu abasebenzisa i-metaboliser kakubi.
Okubalulekileyo kukuba, iSivumelwano seeNgcali zaseTshayina esisandula ukupapashwa malunga noVavanyo lwePharmacogenomic kwiPsychiatry (2025) – esiphuhliswe yiPrecision Medicine Collaboration Group yeChinese Society of Psychiatry – siquka ngokucacileyo iingcebiso ze-CYP2C19 genotyping. Ingxelo yemvumelwano iphawula ukuba iingcebiso zokulungiswa kwedosi ezivela kwizikhokelo zamazwe ngamazwe ezifana neCPIC kunye ne-DPWG ze-metabolising enzymes zamayeza (kubandakanya i-CYP2C19) zinokubhekiselwa kubantu baseTshayina. Ke ngoko, i-CYP2C19 genotyping ngaphambi kokuqalisa unyango lwe-SSRI (umz., i-escitalopram) ivumela ukwenziwa ngcono kwedosi okanye ukutshintshela kwezinye iziyobisi ezingaguqulwanga yi-CYP2C19, ngaloo ndlela kufezekiswa unyango oluchanekileyo, kuphuculwe amazinga okuphendula, kwaye kuncitshiswe iziganeko ezimbi.
2. IiProton Pump Inhibitors (iiPPI)
Izithinteli zeProton pump – kuquka i-omeprazole, i-lansoprazole, kunye ne-pantoprazole – zisetyenziswa kakhulu kwizifo ezinxulumene ne-asidi ezifana nesifo se-gastroesophageal reflux kunye nezilonda ze-peptic. I-metabolism yazo ixhomekeke kakhulu kwi-CYP2C19. Izigulane ezine-genotypes ezahlukeneyo ze-CYP2C19 zibonisa umahluko omkhulu ekuphenduleni kwi-PPIs. Abathwali bokulahlekelwa zii-alleles zomsebenzi (*2, *3) baye banda kakhulu ukuvezwa kweziyobisi, nto leyo enokunyusa ukucinezelwa kwe-asidi kodwa ikwanyusa nomngcipheko wemiphumo emibi. Ngokwahlukileyo koko, ii-metaboliser eziqhelekileyo zinezinga eliphantsi le-plasma kwaye zinokufumana ukucinezelwa kwe-asidi ebuthathaka, nangona umahluko phakathi komntu ngamnye usabonakala umkhulu.
Isikhokelo se-CPIC sika-2020 se-PPIs sicebisa ukuba abantu abasebenzisa i-omeprazole okanye amayeza afanayo ngokukhawuleza basebenzise i-omeprazole ngokukhawuleza kakhulu, nto leyo ebangela ukuba amanqanaba e-plasma anganelanga kunye nokuncitshiswa kwe-asidi embi. Kwezi zigulana, idosi kufuneka inyuswe kwaye impendulo yonyango ijongwe. Kwabo basebenzisa i-metabolizer embi, ukususwa kwamayeza kuhamba kancinci kwaye amanqanaba e-plasma anokuphakama; ngelixa ukusebenza kakuhle kunokuba ngcono, amathuba okuba netyhefu kuyanda. Ukunciphisa idosi kunye nokubeka iliso kwimpendulo zizinto ezifanelekileyo. Ke ngoko, kwizigulane eziqalisa unyango lwe-PPI okanye ezo zifumana impendulo embi okanye iziphumo ezimbi, i-CYP2C19 genotyping iyacetyiswa ukukhokela idosi yomntu ngamnye, ukuphucula ukusebenza kakuhle, kunye nokunciphisa iziganeko ezimbi.
3. I-Voriconazole
I-Voriconazole sisithako esibanzi sokulwa nentsholongwane esisetyenziselwa ukunyanga izifo ezinzulu zefungus ezifana ne-aspergillosis ehlaselayo. Inesithuba esincinci sonyango: amazinga aphezulu kakhulu eplasma anyusa umngcipheko we-hepatotoxicity kunye nokuphazamiseka kokubona, ngelixa amazinga aphantsi ebangela ukungaphumeleli konyango. I-metabolism ye-voriconazole ilawulwa ikakhulu yi-CYP2C19, kwaye ii-polymorphisms ze-genetic zinempembelelo enkulu kumazinga ayo eplasma.
I-CPIC ipapashe isikhokelo esizinikeleyo kwi-CYP2C19 kunye ne-voriconazole ngo-2016. Ithi ii-metaboliser ze-ultrapid ziye zanciphisa uxinano lwe-voriconazole trough kwaye zihlala zisilela ukufikelela kumanqanaba okunyanga ekujoliswe kuwo. Ii-metaboliser ezingalunganga zinezinga eliphezulu loxinano lwe-trough kunye nomngcipheko okhulayo kakhulu weempendulo ezimbi. Isikhokelo se-CPIC sinika iingcebiso ezithile zokulinganisa ngokusekelwe kwi-genotype. Umzekelo, ii-metaboliser zabantu abadala ze-ultrapid trough kufuneka zifumane ezinye ii-arhente zomgca wokuqala ezingaxhomekekanga kwi-metabolism ye-CYP2C19, njenge-isavuconazole, i-liposomal amphotericin B, okanye i-posaconazole. Ke ngoko, i-CYP2C19 genotyping ngaphambi konyango lwe-voriconazole ivumela i-dosing eyenzelwe umntu ngamnye kwaye inciphisa ukwanda kweziganeko ezimbi ezinxulumene namayeza.
Ukubaluleka Kwezonyango: Ukwenza Amayeza Athembeke Ngakumbi
Isikhokelo esisandula ukukhutshwa siphinda sibeke i-CYP2C19 genotyping phambili kunyango oluchanekileyo. Nangona kunjalo, kubalulekile ukuqaphela ukuba ukusetyenziswa kwe-CYP2C19 genotyping kudlula kakhulu i-clopidogrel – ukusuka kwi-voriconazole (i-antifungal) kunye ne-SSRIs (i-antidepressants) ukuya kwi-proton pump inhibitors yokunciphisa i-asidi. I-CYP2C19 genotype isebenza njenge "compass" yonyango lwamayeza.
Njengoko amayeza achanekileyo esiya ethandwa ngokubanzi, inani elikhulayo lezikhokelo ezigunyazisiweyo libandakanya i-CYP2C19 genotyping kwimisebenzi yesiqhelo yamayeza. Kwizigulane, ukwazi i-CYP2C19 genotype yazo kubanceda baqonde iprofayili yazo yokuphendula amayeza kwaye kuvumela ukuba kwenziwe izigqibo kunye nogqirha wabo ukuze benze isicwangciso sonyango esifanelekileyo. Kwabo bagqirha, ukudibanisa iziphumo zovavanyo lwemfuza oluchanekileyo kwizigqibo zokunika amayeza yindlela enamandla yokuphucula umgangatho wonyango kunye nokuqinisekisa ukhuseleko lwezigulane.
Uvavanyo lweMacro kunye nolweMicro'sIsisombululo se-CYP2C19 Genotyping
I-Macro & Micro Test inikezela ngekhithi ye-CYP2C19 genotyping esekwe kwinkqubo yokuguqulwa kwe-amplification refractory mutation (ARMS) ephuculweyo edityaniswe nee-probes zeTaqman ezineempawu ezilandelayo:
-Ukugubungela ngokupheleleyo i-allele– iyafumanisaI-CYP2C192, *3, kunye *17ngaphandle kokulahlekelwa ziinguqulelo ezibalulekileyo.
-Ulawulo lomgangatho oluqinileyo– ibandakanya ulawulo olungalunganga/oluhle, ulawulo lwangaphakathi, kunye ne-enzyme ye-UDG yolawulo lomgangatho olunemigangatho emine ukuqinisekisa iziphumo ezichanekileyo.
-Ukukhupha ngokuzenzekelayo– iyahambelana ne-Macro & Micro-Test's ngokuzenzekelayo ngokupheleleyo i-nucleic acid extractor, ephucula ukusebenza kakuhle komsebenzi.
-Ukuhambelana okubanzi– isebenza nezixhobo zePCR zexesha langempela ezithengiswayo, kuquka i-ABI 7500 Hongshi SLAN 96P.
-Ukutolikwa kweziphumo ngokuzenzekelayo– isoftware yohlalutyo ezinikeleyo (kwi-ABI 7500, SLAN 96P, njl.njl.) ivumela ukutolikwa ngokuzenzekelayo kweziphumo, nto leyo ephucula ukusebenza kakuhle.
-Ukuzenzekelayo okulungiselelwe yi-POCT– I-HWTS AIO800 I-Full Automated Nucleic Acid Amplification Analyzer yenza ukuba kusebenze “isampuli yokungena, iziphumo”.
Ngokuqhubeka nokuqhubela phambili kwe-pharmacogenomics, kulindeleke ukuba i-CYP2C19 genotyping incede inani elikhulayo lezigulane, isusa amayeza achanekileyo ukusuka kwingcamango ukuya kwindlela eqhelekileyo yonyango. Isikhokelo se-CERSI PGx esisandula ukupapashwa siqinisa indima ebalulekileyo yovavanyo lwe-CYP2C19 kungekuphela nje kwi-clopidogrel kodwa nakwiluhlu olukhulayo lwamayeza, kubandakanya amayeza okudakumba, i-proton pump inhibitors, kunye ne-voriconazole. Ukuze kube lula ukwamkelwa ngokubanzi komyalelo okhokelwa yi-genotype, izisombululo zovavanyo ezinokuthenjwa nezisebenziseka lula zibalulekile. Ipotifoliyo yovavanyo lwe-pharmacogenomic ye-Macro & Micro-Test, equka ukugubungela okupheleleyo kwe-allele, ulawulo oluqinileyo lomgangatho, kunye namaqonga okulungela ukwenza izinto ngokuzenzekelayo, ijolise ekuxhaseni ababoneleli bezempilo ekuphunyezweni kwamayeza achanekileyo kwaye ekugqibeleni ikhusele impilo yesigulane.
Iimveliso Ezinxulumeneyo:
Iireferensi:
1.Lima JJ, Thomas CD, Barbarino J, et al. Isikhokelo seClinical Pharmacogenetics Implementation Consortium (CPIC) seCYP2C19 kunye neProton Pump Inhibitor Dosing. Clin Pharmacol Ther. 2020. doi:10.1002/cpt.20151.
2.Lee CR, Luzum JA, Sangkuhl K, et al. Isikhokelo seClinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: Uhlaziyo luka-2022. Clin Pharmacol Ther. 2022. doi:10.1002/cpt.25261.
3. I-National Institute for Health and Care Excellence (NICE). Uvavanyo lwe-CYP2C19 genotype luza kunceda ekusetyenzisweni kwe-clopidogrel emva kwe-ischemic stroke okanye uhlaselo lwe-ischemic olufutshane. Isikhokelo sokuxilongwa kwe-DG59. Ipapashwe: 31 Julayi 2024.
4. Iqela leNtsebenziswano yoPhando lweMithi echanekileyo le-Chinese Society of Psychiatry. Imvumelwano yeengcali malunga novavanyo lwe-pharmacogenomic kwi-psychiatry (2025) [Zhonghua Jing Shen Ke Za Zhi].Ijenali yesiTshayina yezeNgqondo. 2025;58(6):434-445. doi:10.3760/cma.j.cn11366120240611-00181
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7.Bousman CA, Stevenson JM, Ramsey LB, et al. Isikhokelo seClinical Pharmacogenetics Implementation Consortium (CPIC) seCYP2D6, CYP2C19, CYP2B6, SLC6A4, kunye neHTR2A Genotypes kunye neSerotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68. doi:10.1002/cpt.2903.
8.Brouwer JMJL, Nijenhuis M, Soree B, et al. Isikhokelo seDutch Pharmacogenetics Working Group (DPWG) sokusebenzisana kwe-gene-drug phakathi kwe-CYP2C19 kunye ne-CYP2D6 kunye ne-SSRIs. Eur J Hum Genet. 2021. doi:10.1038/s41431-021-00894-2.
Ixesha lokuthumela: Epreli-22-2026