Muva nje, i-British Journal of Clinical Pharmacology ishicilele isiqondiso sokuqala sezokwelapha esakhiwe yi-UK Centre of Excellence for Regulatory Science and Innovation in Pharmacogenomics (CERSI PGx), esinesihloko esithi “Ukuhlolwa kwe-genotype ye-CYP2C19 ye-clopidogrel: Isiqondiso esakhiwe yi-UK Centre of Excellence yesayensi yokulawula kanye nokusungula izinto ezintsha ku-pharmacogenomics (CERSI PGx)”. Lo mbhalo obalulekile ugxile ekubalukeni kwezokwelapha kwe-CYP2C19 genotyping ekwelapheni i-clopidogrel eqondisayo.
Mayelana ne-CERSI PGx
I-CERSI PGx ingenye yezikhungo eziyisikhombisa zesayensi nobuchwepheshe obusekelwe uhulumeni wase-UK ezasungulwa ngoJanuwari 2025. Iholwa yi-University of Liverpool, ixhaswe ngokubambisana yi-Innovate UK, i-Medical Research Council (MRC), i-Medicines and Healthcare products Regulatory Agency (MHRA), kanye ne-Office for Life Sciences (OLS). Lesi sikhungo sihlose ukusheshisa ukuhlanganiswa okuphephile nokuphumelelayo kwe-pharmacogenomics (PGx) kwi-National Health Service (NHS) ngokubhekana nezithiyo ezibalulekile zokuqaliswa. Lesi siqondiso siphawula isiqondiso sokuqala sezokwelapha esikhishwe selokhu kwasungulwa i-CERSI PGx.
Kungani i-CYP2C19 Ibalulekile ku-Clopidogrel
I-CYP2C19 iyilungu elibalulekile lomndeni wama-enzyme e-cytochrome P450, elibhekene nokusebenza kwe-metabolic noma ukungasebenzi kwemithi eminingi. Ama-polymorphisms ezakhi zofuzo ku-CYP2C19 aholela ekwehlukeni okukhulu phakathi kwabantu ngabanye ekusetshenzisweni kwemithi, okuthinta ukusebenza kahle kanye nokuphepha.
I-Clopidogrel iyi-antiplatelet esetshenziswa kabanzi ekuvimbeleni izehlakalo ze-thrombotic ezifweni ze-coronary artery, i-ischemic stroke, isifo se-peripheral artery, kanye ne-atrial fibrillation. Njengomuthi oyinhloko, i-clopidogrel idinga ukusebenza kwe-metabolic yi-CYP2C19. Lo mhlahlandlela uhlukanisa abantu babe ngama-metaboliser asheshayo, asheshayo, ajwayelekile, aphakathi, kanye nampofu ngokusekelwe ku-genotype ye-CYP2C19. Abathwali bokulahlekelwa ama-alleles okusebenza (isb., i-CYP2C192 kanye ne-*3*) - ama-metaboliser aphakathi kanye nampofu - abakwazi ukwenza i-clopidogrel isebenze ngempumelelo, okuholela ekuvinjelweni kwe-platelet okunganele kanye nengozi eyengeziwe ye-thrombosis ephindaphindayo.
Imvamisa ye-allele ye-CYP2C192 cishe ingu-15% kubantu baseYurophu, ingu-30% kubantu baseNingizimu Asia, futhi ifinyelela ku-60% kubantu bomdabu base-Ocean.
Isincomo Esiyinhloko: Ukuhlolwa kwe-CYP2C19 okujwayelekile kwe-Clopidogrel
Isiqondiso sithi, kungakhathaliseki ukuthi izinkomba ziyini, bonke iziguli okucatshangelwa kuzo i-clopidogrel kufanele zithathe umuthi.I-CYP2C19ukwakheka kwezakhi zofuzo.Ngokusekelwe emiphumeleni, ukwelashwa kwe-antiplatelet kufanele kwenziwe ngcono:
-Ama-metaboliser ampofukufanele bagweme i-clopidogrel futhi bakhethe ukusebenzisa ezinye izidakamizwa ezingaxhomekile kumetabolism ye-CYP2C19, njenge-ticagrelor noma i-prasugrel.
-Ama-metaboliser aphakathi nendawokufanele futhi ucabangele ezinye izindlela zokwelapha noma izindlela zokwelapha ezilungisiwe kunokwandisa umthamo we-clopidogrel.
E-UK, i-clopidogrel ivunyelwe ukuvimbela okwesibili izehlakalo ze-atherothrombotic, ukuhlasela kwe-ischemic okulinganiselwe kuya kokuphezulu okuyingozi (i-TIA) noma i-stroke encane ye-ischemic, kanye nokuvimbela izehlakalo ze-atherothrombotic kanye ne-thromboembolic ku-atrial fibrillation.
Ngale kwe-Clopidogrel: Eminye Imithi Lapho Ukuhlolwa Kwezakhi Zofuzo ze-CYP2C19 Kubaluleke Kakhulu
Inani le-CYP2C19 genotyping lidlulela ngale kwe-clopidogrel. Njenge-enzyme enkulu eguqula umuthi, i-CYP2C19 idlala indima ebalulekile ekusetshenzisweni kwe-voriconazole, ama-antidepressants amaningana, kanye nama-proton pump inhibitors (PPIs). Iziqondiso eziningi zamazwe ngamazwe nezesizwe zincoma ukwenziwa komuntu ngamunye okuqondiswa yi-genotype yale mithi.
1. Ama-antidepressants (ama-SSRI)
Ama-Selective serotonin reuptake inhibitors (SSRIs) – njenge-sertraline, i-citalopram, kanye ne-escitalopram – ayizinto zokuqala ezibangela ukucindezeleka futhi ngokuyinhloko aguqulwa yi-CYP2C19. Umsebenzi we-enzyme ye-CYP2C19 unquma ngqo ukuhlushwa kwale mithi egazini. Ama-metaboliser ampofu anokwehla okungu-30%–60% ekususweni kwemithi, okuwabeka engozini yokuthola imiphumela emibi njengokwandiswa kwesikhathi se-QT kanye nokudambisa. Ama-metaboliser asheshayo avame ukuba nokuhlushwa kwe-plasma okungaphansi kokwelashwa, okuholela ekwephuzeni kokwelashwa kanye nengozi eyengeziwe yokuyeka imithi.
Isiqondiso se-Clinical Pharmacogenetics Implementation Consortium (CPIC) sika-2023 sithi ama-metaboliser ampofu athatha i-citalopram noma i-escitalopram anengozi ephezulu yokwandiswa kwe-QT futhi sincoma ukwehliswa komthamo ngo-50%. Isiqondiso se-Dutch Pharmacogenetics Working Group (DPWG) sika-2021 seluleka ukuthi ama-metaboliser ampofu kufanele athole umthamo omkhulu we-escitalopram oncishiswe ngo-50%, nokuthi ama-metaboliser asheshayo kufanele agweme i-escitalopram ngokuphelele. Ku-sertraline, i-DPWG incoma umthamo wansuku zonke ongadluli u-75 mg kuma-metaboliser ampofu.
Okubalulekile, i-Chinese Expert Consensus on Pharmacogenomic Testing in Psychiatry (2025) esanda kushicilelwa – eyathuthukiswa yi-Precision Medicine Collaboration Group ye-Chinese Society of Psychiatry – ifaka ngokusobala izincomo ze-CYP2C19 genotyping. Isitatimende sokuvumelana siphawula ukuthi izincomo zokulungiswa komthamo ezivela eziqondisweni zomhlaba wonke ezifana ne-CPIC kanye ne-DPWG zama-enzyme aguqula umuthi (kufaka phakathi i-CYP2C19) zingabhekiselwa kubantu baseShayina. Ngakho-ke, i-CYP2C19 genotyping ngaphambi kokuqala ukwelashwa kwe-SSRI (isb., i-escitalopram) ivumela ukwenziwa ngcono komthamo noma ukushintshela kwezinye izidakamizwa ezingaguqulwanga yi-CYP2C19, ngaleyo ndlela kufezwe ukwelashwa okunembile, kuthuthukiswe amazinga okuphendula, futhi kuncishiswe izehlakalo ezimbi.
2. Ama-Proton Pump Inhibitors (PPI)
Ama-proton pump inhibitors – kufaka phakathi i-omeprazole, i-lansoprazole, kanye ne-pantoprazole – asetshenziswa kabanzi ezifweni ezihlobene ne-asidi njengesifo se-gastroesophageal reflux kanye nezilonda ze-peptic. I-metabolism yabo incike kakhulu kwi-CYP2C19. Iziguli ezinezinhlobo ezahlukene ze-CYP2C19 genotypes zibonisa ukuguquguquka okukhulu ekuphenduleni ama-PPI. Abathwali bokulahlekelwa ama-alleles okusebenza (*2, *3) baveze kakhulu izidakamizwa, okungase kuthuthukise ukucindezelwa kwe-asidi kodwa futhi kukhulise ingozi yemiphumela emibi. Ngokuphambene nalokho, ama-metaboliser avamile anokuhlushwa okuphansi kwe-plasma futhi angase abhekane nokucindezelwa kwe-asidi okubuthakathaka, yize ukuhlukahluka phakathi kwabantu ngabanye kusalokhu kukhulu.
Isiqondiso se-CPIC sika-2020 sama-PPI seluleka ukuthi ama-metaboliser asebenzisa i-omeprazole noma imithi efanayo ngokushesha kakhulu asebenzise umuthi ngokushesha kakhulu, okuholela ekunganele kwamazinga e-plasma kanye nokucindezelwa kwe-asidi okungekuhle. Kulezi ziguli, umthamo kufanele ukhushulwe futhi impendulo yokwelapha iqashwe. Kwabasebenzisa ama-metaboliser abangekuhle, ukususwa kwemithi kuhamba kancane futhi amazinga e-plasma angase aphakame; ngenkathi ukusebenza kahle kungaba ngcono, amathuba okuba yingozi kwemithi ayanda. Ukunciphisa umthamo kanye nokuqapha impendulo kuyizinto ezinengqondo okufanele zicatshangelwe. Ngakho-ke, ezigulini eziqala ukwelashwa kwe-PPI noma lezo ezithola impendulo engenhle noma imiphumela emibi, i-CYP2C19 genotyping iyanconywa ukuze iqondise umthamo ozimele, ithuthukise ukusebenza kahle, futhi inciphise izehlakalo ezimbi.
3. I-Voriconazole
I-Voriconazole iyi-ejenti ebanzi ye-antifungal esetshenziselwa ukwelapha izifo ezinkulu ze-fungus njenge-aspergillosis ehlaselayo. Inefasitela elincane lokwelapha: amazinga aphezulu kakhulu e-plasma andisa ingozi yobuthi besibindi kanye nokuphazamiseka kokubona, kuyilapho amazinga aphansi eholela ekwehlulekeni kokwelashwa. I-metabolism ye-voriconazole iqondiswa kakhulu yi-CYP2C19, futhi ama-polymorphisms ezakhi zofuzo anomthelela omkhulu ekugxilweni kwayo e-plasma.
I-CPIC yashicilela isiqondiso esizinikele ku-CYP2C19 kanye ne-voriconazole ngo-2016. Ithi ama-metaboliser asheshayo anciphise amazinga e-voriconazole trough futhi avame ukwehluleka ukufinyelela amazinga okwelapha aqondiwe. Ama-metaboliser ampofu anomazinga aphezulu e-trough kanye nengozi ekhulayo kakhulu yokusabela okubi. Isiqondiso se-CPIC sinikeza izincomo ezithile zokulinganisa ngokusekelwe kuhlobo lwe-genotype. Isibonelo, ama-metaboliser ama-high e-ultrapid abantu abadala kufanele bathole ama-ejenti okuqala angaxhomekile ku-metabolism ye-CYP2C19, njenge-isavuconazole, i-liposomal amphotericin B, noma i-posaconazole. Ngakho-ke, i-CYP2C19 genotyping ngaphambi kokwelashwa kwe-voriconazole ivumela ukukala komuntu ngamunye futhi kunciphisa izehlakalo ezimbi ezihlobene nemithi.
Ukubaluleka Kwezokwelapha: Ukwenza Imithi Ithembeke Kakhulu
Isiqondiso esisanda kukhishwa siphinde sibeka i-CYP2C19 genotyping phambili kwezokwelapha ngokunemba. Kodwa-ke, kubalulekile ukuqaphela ukuthi ukusetshenziswa kwezokwelapha kwe-CYP2C19 genotyping kudlulela ngale kwe-clopidogrel - kusukela ku-voriconazole (antifungal) kanye nama-SSRI (ama-antidepressants) kuya kuma-proton pump inhibitors okunciphisa i-asidi. I-CYP2C19 genotype isebenza njenge-"compass" yokwelapha ngemithi.
Njengoba imithi enembile ithola ukwamukelwa kabanzi, inani elikhulayo leziqondiso ezigunyaziwe lifaka i-CYP2C19 genotyping emisebenzini ejwayelekile yemithi. Ezigulini, ukwazi i-CYP2C19 genotype yazo kubasiza baqonde iphrofayili yabo yokusabela emithini ngayinye futhi kwenza kube lula ukwenza izinqumo ezihlanganyelwe nodokotela wabo ukuthuthukisa uhlelo lokwelapha olufaneleka kakhudlwana. Kwabodokotela, ukuhlanganisa imiphumela yokuhlolwa kwezakhi zofuzo eqondile ezinqumweni zokunikeza imithi kuyindlela enamandla yokuthuthukisa ikhwalithi yokwelashwa nokuqinisekisa ukuphepha kwesiguli.
Ukuhlolwa Okukhulu Nokuncane'sIsixazululo Sokuhlonza Izakhi Zofuzo se-CYP2C19
I-Macro & Micro Test inikeza ikhithi yohlobo lwe-CYP2C19 esekelwe ohlelweni lokuguqulwa kwe-amplification refractory oluthuthukisiwe (i-ARMS) oluhlanganiswe nama-probe e-Taqman anezici ezilandelayo:
-Ukumbozwa okuphelele kwe-allele- kutholaI-CYP2C192, *3, kanye *17ngaphandle kokulahlekelwa izinhlobo eziyinhloko.
-Ukulawulwa kwekhwalithi okuqinile– ifaka izilawuli ezingezinhle/ezimbi, ukulawula kwangaphakathi, kanye ne-enzyme ye-UDG yokulawula ikhwalithi yezinga ezine ukuqinisekisa imiphumela enembile.
-Ukukhipha okuzenzakalelayo– iyahambisana ne-Macro & Micro-Test's ezenzakalelayo ngokuphelele i-nucleic acid extractor, ethuthukisa ukusebenza kahle komsebenzi.
-Ukuhambisana okubanzi– isebenza nezinsimbi ze-PCR zesikhathi sangempela ezivamile emakethe, okuhlanganisa ne-ABI 7500 Hongshi SLAN 96P.
-Ukuhumusha imiphumela okuzenzakalelayo– isofthiwe yokuhlaziya ezinikele (ku-ABI 7500, SLAN 96P, njll.) ivumela ukuhumusha okuzenzakalelayo kwemiphumela, okuthuthukisa ukusebenza kahle.
-Ukuzenzakalela okulungele i-POCT– I-HWTS AIO800 I-Nucleic Acid Amplification Analyzer Ezenzakalelayo Ngokugcwele ivumela ukusebenza "kokufaka isampula, ukuphuma".
Ngokuthuthuka okuqhubekayo kwe-pharmacogenomics, i-CYP2C19 genotyping kulindeleke ukuthi izuzise inani elikhulayo leziguli, isusa umuthi onembile kusuka emqondweni iye ekusebenzeni okuvamile kwezokwelapha. Umhlahlandlela we-CERSI PGx osanda kushicilelwa uqinisa indima ebalulekile yokuhlolwa kwe-CYP2C19 hhayi nje kuphela kwe-clopidogrel kodwa futhi nohlu olukhulayo lwemithi, okuhlanganisa ama-antidepressants, ama-proton pump inhibitors, kanye ne-voriconazole. Ukuze kube lula ukwamukelwa kabanzi kokunikezwa kwemithi okuqondiswa yi-genotype, izixazululo zokuhlola ezinokwethenjelwa nezisebenziseka kalula zibalulekile. Iphothifoliyo yokuhlola i-pharmacogenomic ye-Macro & Micro-Test, equkethe ukumbozwa okuphelele kwe-allele, ukulawulwa kwekhwalithi okuqinile, kanye namapulatifomu alungele ukwenza izinto ngokuzenzakalela, ihlose ukusekela abahlinzeki bezempilo ekusebenziseni umuthi onembile futhi ekugcineni bavikele impilo yeziguli.
Imikhiqizo Ehlobene:
Izinkomba:
1.Lima JJ, Thomas CD, Barbarino J, nabanye. Umhlahlandlela we-Clinical Pharmacogenetics Implementation Consortium (CPIC) wokulinganisa i-CYP2C19 kanye ne-Proton Pump Inhibitor Dosing. Clin Pharmacol Ther. 2020. doi:10.1002/cpt.20151.
2.Lee CR, Luzum JA, Sangkuhl K, nabanye. Umhlahlandlela Wokusetshenziswa Kwe-Clinical Pharmacogenetics Consortium we-CYP2C19 Genotype kanye ne-Clopidogrel Therapy: Isibuyekezo sika-2022. Clin Pharmacol Ther. 2022. doi:10.1002/cpt.25261.
3. I-National Institute for Health and Care Excellence (NICE). Ukuhlolwa kwe-genotype ye-CYP2C19 ukuqondisa ukusetshenziswa kwe-clopidogrel ngemva kokuhlaselwa yi-ischaemic noma ukuhlaselwa yi-ischaemic okwesikhashana. Isiqondiso sokuxilonga i-DG59. Kushicilelwe: 31 Julayi 2024.
4. Iqembu Lokubambisana Locwaningo Lwezokwelapha Oluqondile le-Chinese Society of Psychiatry. Ukuvumelana kochwepheshe ngokuhlolwa kwe-pharmacogenomic kwezokwelapha kwengqondo (2025) [Zhonghua Jing Shen Ke Za Zhi].Ijenali Yezokwelapha Yengqondo YaseShayina. 2025;58(6):434-445. doi:10.3760/cma.j.cn11366120240611-00181
5.Dello Russo C, Frater I, Kuruvilla R, nabanye. Ukuhlolwa kwe-genotype ye-CYP2C19 ye-clopidogrel: Isiqondiso esakhiwe yi-UK Centre of Excellence yesayensi yokulawula kanye nokusungula izinto ezintsha ku-pharmacogenomics (CERSI-PGx). Br J Clin Pharmacol. 2025. DOI: 10.1093/bjcp/…
6.Moriyama B, Owusu Obeng A, Barbarino J, nabanye. Imihlahlandlela ye-Clinical Pharmacogenetics Implementation Consortium (CPIC) ye-CYP2C19 kanye ne-Voriconazole Therapy. Clin Pharmacol Ther. 2017;102(1):45-51. doi:10.1002/cpt.595.
7.Bousman CA, Stevenson JM, Ramsey LB, nabanye. Umhlahlandlela we-Clinical Pharmacogenetics Implementation Consortium (CPIC) we-CYP2D6, CYP2C19, CYP2B6, SLC6A4, kanye ne-HTR2A Genotypes kanye ne-Serotonin 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. Isiqondiso se-Dutch Pharmacogenetics Working Group (DPWG) sokusebenzisana kwezakhi zofuzo nezidakamizwa phakathi kwe-CYP2C19 ne-CYP2D6 nama-SSRI. Eur J Hum Genet. 2021. doi:10.1038/s41431-021-00894-2.
Isikhathi sokuthunyelwe: Ephreli-22-2026