Popeza mankhwala osokoneza bongo a enzyme amachepetsa pang'onopang'ono ndi kutalika kwa nthawi yoyamwitsa m'mimba, zitsanzo zamtundu wa m'mimba za m'mimba zimakhala ndi malire monga nthawi yaifupi ya makulitsidwe, kutembenuka kochepa kwa kagayidwe kachakudya ndi kutsika kwakukulu kwa kuzindikira (kuchuluka kwa malire a CLint assay ndi 2.5 μL / ( min · 106 maselo) ), omwe sangathe kufotokoza molondola za mankhwala a CLl[1]. Pakadali pano,hepatocyteAli ndi ma enzymes ambiri ofunikira kuti makutidwe ndi okosijeni, kuchepetsa, hydrolysis ndi dimerization reaction poyerekeza ndima microsomes a chiwindi, ndi machitidwe a in vitro, mitundu yambiri yaposachedwa imakhala yokongoletsedwa kutengerahepatocyte dongosolo ndikutsanziranso mu vivo chilengedwe kuti mutalikitse kusungidwa kwa enzymehepatocytes, komanso kutalika kwa nthawi yoyamwitsa kumapereka mwayi wowunika kusintha kwa kagayidwe kachakudya kamankhwala ochepetsa kagayidwe kazakudya.[1, 2].
Poganizira izi, IPHASE, monga mtsogoleri wa tizilombo toyambitsa matenda pa kafukufuku wa mu vitro, yakhala upainiya wa HepatoMax™ System ndi HepatoCon™ Media System pogwiritsa ntchito kafukufuku wa hepatocytes oyambirira ndi maselo a stromal amitundu yosiyanasiyana, kuphatikizapo anthu, nyani, canine, makoswe, ndi mbewa, ndi zina zotero.hepatocyteMwachitsanzo, machitidwe onsewa adakhazikitsidwa kuti adziwe momwe ntchitoyi ikuyendera komanso kukhazikika kwa kagayidwe kachakudya chamitundu yeniyeni ya michere komanso kuchuluka kwa mayankho a metabolites a tolbutamide pamasiku 10 ndi masiku 7 kuti atsimikizire machitidwe. Metabolite imachulukitsa kuyankha pamasiku a 10 ndipo ntchito ndi kukhazikika kwa metabolic kwa mitundu ina ya ma enzyme pamasiku 7 zidatsimikizika kuti zitsimikizire machitidwewo.
- (1) Njira ziwiri zovomerezeka zovomerezeka zamankhwala ndi izi:
IPHASE-HepatoMax™ndi njira yachikhalidwe ya ma hepatocyte amunthu oundana okhala ndi mipanda ndi ma cell a stromal. Ma hepatocyte a anthu oyambirira adatsitsimutsidwa ndikuphatikizidwa ndi maselo a stromal mu HepatoP ™ sing'anga kwa masiku a 3 kuti ayambe kuyesa kayendetsedwe ka mankhwala, ndipo kagayidwe ka mankhwala kameneka kankachitika mu serum-free HepatoDo™ medium, yomwe inangowonjezeredwa ndi mankhwala popanda kusintha sing'anga. Chiwerengero cha 4, 72, 168 ndi 240 maola pambuyo poyendetsa mankhwala, mtengo wowonjezera wa metabolites wa mankhwala unatsimikiziridwa kuti awunike.
IPHASE-HepatoCon™Komano, ndi njira yopangira ma hepatocyte aanthu owuma mu HepatoCon™ medium. Pambuyo pa kuukitsa munthu woyambahepatocytes, kuyesa kwa mankhwala osokoneza bongo kunachitika pambuyo pa masiku a 3 a chikhalidwe mu HepatoCon ™ medium yokha, ndipo nthawi yotsatila, chikhalidwe cha chikhalidwe ndi njira zoyesera zinali zofanana ndi za HepatoMax ™ system.
Panthawiyi, kuti zitsimikizire kuti zotsatira zake ndi zolondola komanso zokhwima, IPHASE inachita kulamulira kwapakatikati (cell - free) ndi stromal cell control panthawi imodzimodzi, ndi kubwereza katatu, ndipo zotsatira zimasonyeza kutiIPHASE-HepatoMax™ ndiIPHASE-HepatoCon™ machitidwe adatulutsa kuyankha kwamphamvu kwa metabolite kuyambira tsiku la 3 kupita mtsogolo, ndikuti onse adawonetsa chiwopsezo champhamvu cha metabolic.
- (2) Mankhwala a metabolism amadalira kwambiri hepatocyteMtengo wa CYP450ma enzyme system, ndi ntchito yake imatha kuyesedwa kuti iwunike bwino.
TheIPHASE-HepatoMax™ ndiIPHASE-HepatoCon™ ndondomekoyi ndi yabwino kugwiritsa ntchito.
IPHASE idakhazikitsa magulu anayi apakati (palibe ma cell), HepatoMax™, HepatoCon™ ndi ma cell a stromal. Kugwiritsa ntchito khoma-otsatira munthu woyambahepatocyteMwachitsanzo, kuchuluka kwa metabolite kumawonjezekaChithunzi cha CYP1A2, Chithunzi cha CYP2B6ndiChithunzi cha CYP3A4adatsimikiziridwa tsiku la 0, 3 ndi 7 pambuyo pakehepatocytekuchira kwa masiku atatu pogwiritsa ntchito finasteride, bupropion ndi midazolam monga gawo lapansi, motero. Kuwonjezeka kwa metabolite kumawonetsa kuti zonseziIPHASE-HepatoMax™ ndiIPHASE-HepatoCon™ machitidwe adawonetsa zochitika zogwira ntchito za enzyme pofika tsiku la 7, zomwe zimalimbikitsa kagayidwe wamba wamankhwala.
- (3) Kuphatikiza pa kutsimikizira ntchito ya ma enzyme, kukhazikika kwabwino kwa metabolic ndi gawo lofunikira komanso lofunikira pakutsimikizira kugwiritsa ntchito mitundu ya in vitro.
IPHASE inakhazikitsa magulu atatu a HepatoMax™, HepatoCon™ ndi maselo a stromal kuti adziwe kukhazikika kwa kagayidwe kachakudya kwa Tolbutimide pa nthawi ya maola 80 pogwiritsa ntchito hepatocytes yoyambirira yaumunthu monga chitsanzo, yomwe inaperekedwa patatha masiku 3 kutsitsimula kwa pulayimale.hepatocytes, ndipo zotsatira zake zikuwonetsa kuti onse awiriIPHASE-HepatoMax™ ndiIPHASE-HepatoCon™ machitidwe onsewa adawonetsa zochitika zamphamvu za metabolic mkati mwa mtengo wautali kwambiri wanthawi yoyeserera.
Mwachidule, IPHASE, monga mtsogoleri mu vitro bio-reagents, yapangaIPHASE HepatoMax™ ndiIPHASE HepatoCon™ mu vitro zotengera khoma-zinayikapo anthu, nyani, canine, makoswe ndi mbewahepatocytema cell ndi ma stromal amitundu yosiyanasiyana, omwe ali ndi kusintha kwabwino kwambiri kwa kagayidwe kachakudya, zochitika zogwira ntchito za enzyme komanso ntchito zamphamvu zoletsa kagayidwe kachakudya, zomwe zimapereka zosankha zatsopano kwa makasitomala athu kupanga mankhwala otsika - TheIPHASE HepatoMax™ ndiIPHASE HepatoCon™ Mitundu ya in vitro imapereka chiwongola dzanja chabwino kwambiri cha kagayidwe kachakudya, zochitika zogwira ntchito za michere ndi ntchito zolimba za metabolic, zomwe zimapereka zosankha zatsopano kwa makasitomala kuti apange mankhwala otsika-ovomerezeka, ndipo ndi othandizana nawo pakupeza mankhwala!
Zolozera:
[1]阮婷婷,鞠武建,熊海伟,等.低清除率药物的代谢稳定性预测模型研究进中展展[J]. 2019 (2): 152 - 160.
[2] Di L, Trapa P, Obach R S, et al. Njira yatsopano yolumikizirana yodziwira zotsika-zovomerezeka[J]. Mankhwala a metabolism ndi mawonekedwe, 2012, 40 (9): 1860 - 1865.
Nthawi yotumiza: 2024 - 07 - 19 17:20:41