A cikin Vitro Evaluation of In Vitro Drug Transport: Bincika Matsayin ABC Vesicles da SLC Transporter Cells

Mahimman kalmomi: ATP - kaset mai ɗauri (ABC), ABC Transporter, SLC Transporter, Membrane Vesicle, MDR1 (P - gp), BSEP, BCRP, MATE1, MATE2-K, OAT1, OATP1B1, MDCK II, Caco - 2, Hani na Transport, Transporter Substrate Identification, Draug Interaftid1 Dr. HEK293 MOCK, MOCK SLC Transport.

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Fage

A aikace-aikace na asibiti marasa lafiya sukan yi amfani da magunguna da yawa a lokaci guda, kuma waɗannan magungunan na iya haifar da mu'amalar magunguna (DDI) waɗanda ke da yuwuwar haifar da munanan halayen ko canza tasirin magani. Kima na DDI yawanci yana farawa tare da gwajin in vitro don gano abubuwan da zasu iya shafar yanayin ƙwayoyi don bayyana yuwuwar hanyoyin DDI da samun sigogin motsi don ƙarin bincike. Magungunan metabolizing enzymes sun daɗe suna mayar da hankali kan binciken DDI. A cikin 'yan shekarun nan, tare da haɓaka fasahar ilimin halitta, an sami gagarumin ci gaba a cikin nazarin masu safarar magunguna a cikin vitro, kuma mahimmancin kimantawa na in vitro na DDIs masu jigilar kayayyaki ya jawo hankali.

Masu sufuri da Matsayinsu

Transporter yana nufin sunadaran transmembrane a ko'ina cikin tantanin halitta na kyallen takarda daban-daban waɗanda ke yin tsaka-tsakin shigarwa da fita na abubuwan da ba su da kyau ko na waje a ciki da kuma fita daga cikin membranes na halitta. Mai safarar miyagun ƙwayoyi a cikin in vitro kalma ce ta gabaɗaya don sunadaran da ke ɗaukar kwayoyi azaman abubuwan maye, suna wanzuwa a saman sel membrane na kyallen takarda ko gabobin, kuma suna ɗaukar aikin jigilar magungunan transmembrane, galibi gami da iyalai biyu: ATP - kaset mai ɗaure (ABC)superfamily da solute carrier superfamily (SLC Transport), wanda ke mamaye tsarin jigilar magunguna na transmembrane.

Masu sufurin ABCsu ne ATP - masu jigilar kayayyaki masu dogaro da kai waɗanda ke motsawa daban-daban (misali, ions, lipids, da kwayoyi) a cikin membranes tantanin halitta, galibi akan matakan maida hankali. Suna taka muhimmiyar rawa a cikin juriya na miyagun ƙwayoyi, metabolism, da lalatawar salula.SLC masu jigilar kayagalibi masu aiki na sakandare ne ko sauƙaƙe masu jigilar kayayyaki waɗanda ke daidaita motsi na solutes kamar su glucose, amino acid, da neurotransmitters. Ba kamar masu jigilar ABC ba, ba sa buƙatar ATP kai tsaye amma suna dogara ga ion gradients.

Masu sufurin da ke magance zubar da jini sun haɗa da P-glycoprotein (P - gp), ko Multi Su mambobi ne na dangin jigilar kaya na ATP-binding cassette (ABC), waɗanda ke amfani da makamashin ATP na ruwa don jigilar magunguna da abubuwan da ke cikin jiki. Masu sufurin da ke daidaita shigar da kwayoyi a cikin tantanin halitta na iya ɗaukar kayan aiki zuwa wurin da aka yi niyya don aiwatar da tasirin magunguna, kuma suna cikin membobin dangin solute Transport, galibi ciki har da Organic anion transporting polypeptide (OATPs), Organic anion transporter (OATs), Multidrug and toxin extrusion proteins (MATEs), Organic cation transporter (OCTs da dai sauransu).

Manyan Masu Sufuri da Ayyukansu:

• -BSEP(Tsarin Fitar da Gishiri na Bile):Mahimmanci ga ƙwayar bile acid a cikin hanta, rashin aikin BSEP yana da alaƙa da cutar hanta cholestatic. Magunguna
• -BCRP(Protein Resistance Cancer):BCRP yana rinjayar bioavailability na chemotherapeutics da antivirals, fitar da sinadarai daga sel da kuma tasiri ga placental da jini - shiga cikin shingen kwakwalwa.
• -MATE1/MATE2-K(Multidrug da Toxin Extrusion Proteins):Ana zaune a cikin kyallen ƙwayar koda da hanta, MATE1 da MATE2-K excrete cationic kwayoyi, suna aiki tare tare da OCT2 don daidaita ƙwayar koda.
• -Saukewa: OATP1B1(SLCO1B1):Mai ɗaukar hanta mai mahimmanci don cirewar statin. OATP1B1 yana taka muhimmiyar rawa wajen daidaita abubuwan da ke tattare da kwayoyin halitta irin su bilirubic acid, bilirubin, steroid - mahadi guda biyu, da hormones na thyroid, da kuma kawar da hanta daga nau'ikan magungunan asibiti irin su statins, maganin rigakafi, antivirals, da magungunan anticancer.
• -OAT1(SLC22A6):Yana daidaita shan koda na anions, gami da antivirals da NSAIDs, suna tasiri haɗarin nephrotoxicity.

Hana jigilar kayayyaki da DDI

Hana masu sufuriwani muhimmin al'amari ne na ci gaban ƙwayoyi. Hana mai jigilar kayayyaki yana taka muhimmiyar rawa a cikin mu'amalar magunguna (DDI) ta hanyar shafar sha, rarrabawa, metabolism, da fitar da magungunan da ake gudanarwa. Hana masu jigilar kaya irin su MDR1(P-gp) da BCRP na iya rage fitar da kwayoyi na salula, wanda zai iya haifar da mafi girma a cikin salula da kuma tsarin tsarin. Hakazalika, hana masu safarar kayan abinci kamar OATP1B1 na iya rage izinin maganin hanta, yayin da hana BSEP zai iya tsoma baki tare da jigilar bile acid, yana haɓaka haɗarin cholestasis. Bugu da ƙari, masu jigilar kaya kamar MATE1, MATE2-K, da OAT1, waɗanda ke da mahimmanci don kawar da magungunan koda, lokacin da aka hana su, na iya canza fitar da koda da kuma ba da gudummawa ga tarin ƙwayoyi. In vitro model, ciki har daMDCK IIkumaCaco-2layin salula, ana amfani da su sosai don kimanta waɗannan hulɗar jigilar kayayyaki, suna ba da mahimman bayanai game da yuwuwar DDI yayin haɓakar ƙwayoyi.

A cikin Vitro Model don Nazarin Sufuri

Fahimtar aikin jigilar kaya da tsinkayar jigilar kaya - DDI masu tsaka-tsaki sun dogara da keɓaɓɓun ƙirar tantanin halitta. Masu bincike suna amfani da suHEK293 KYAUTAsel a matsayin iko mara kyau, tabbatar da cewa duk wani jigilar da aka lura ya kasance saboda takamaiman mai ɗaukar hoto. HEK293 MOCK yana ba da daidaitaccen bango, yayin da HEK293 MOCK ya kasance tsakiyar tabbatar da ƙayyadaddun gwaji. Hanya ɗaya tana aikimembrane vesiclesdaga sel masu wuce gona da iri, waɗanda galibi ke ware su daga sel HEK293 MOCK. Hakazalika,MOCK SLC Transportersamfura suna da mahimmanci don bambance takamaiman ayyukan jigilar kaya daga ɗaukan da ba na musamman ba. Gwaje-gwajen Motoci na MOCK SLC sun tabbatar da cewa motsin da aka lura yana jigilar kaya - dogaro, kuma gwaje-gwajen Motoci na MOCK SLC suna ƙarfafa amincin samfurin. Wannan tsarin bibiyu ta amfani da HEK293 MOCK da MOCK SLC Transporter yana haɓaka ikon mu na nazarin ATP - jigilar abin dogaro ba tare da tsangwama daga metabolism na salula ba.

Layin tantanin halitta na Caco-2, wanda aka samo daga ciwon daji na hanji na ɗan adam, wani ma'auni ne na yau da kullun da ake amfani da shi don kwaikwaya sha miyagun ƙwayoyi na hanji. Ƙarfinsa na bambancewa cikin enterocyte-kamar sel waɗanda ke bayyana masu jigilar kayayyaki daban-daban-kamar P-gp da BCRP-ya sa ya zama mai ƙima don tantance ƙimar ƙwayar cuta da yuwuwar hulɗar.

Bugu da ƙari, masu jigilar kayayyaki - ƙayyadaddun samfura kamar Human BCRP Bayyanawa sel suna ba da damar bincika takamaiman ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙwayar cuta, halayen motsa jiki na jigilar ƙwayoyi, da gwargwadon abin da masu hanawa zasu iya daidaita ayyukan jigilar kaya. Lokacin da aka haɗa su tare da bayanai daga gwaje-gwajen vesicular, waɗannan tsarin salula suna ba da cikakkiyar fahimta game da ƙarfin jigilar mai-tsatsayin yanayin miyagun ƙwayoyi.

Kammalawa

A taƙaice, fahimtar hulɗar jigilar kayayyaki yana da mahimmanci don inganta amincin ƙwayoyi da inganci. Masu sufuri irin su MDR1 (P - gp), BCRP, da BSEP tare da masu jigilar kayayyaki kamar OATP 1B1 da OAT1 slc Transporter suna taka muhimmiyar rawa a cikin magungunan ƙwayoyi. Amfani da in vitro model ciki har da MDCK II, Caco - 2, Human BCRP Bayyana Kwayoyin, da Human MDR1 Knockin MDCK II Kwayoyin samar da wani m tsarin don fahimtar yadda abin hawa hanawa zai iya shafar miyagun ƙwayoyi-magungunan mu'amala da kuma gaba daya miyagun ƙwayoyi hali. Waɗannan bayanan suna da kima don haɓaka inganci da aminci a cikin saitunan asibiti.