Mu kuwunika kwa Vitro ku Vitro Mankhwala Osokoneza bongo: Kufufuza maudindo a ABC Vessicles ndi SLC Kuyendetsa Maselo

Mawu osakira: ATP - Cassette (ABC), ABC Kuyendetsa, Mdmby, OATP1B1, OAT1 Hek293 mock, mock slurer.

Zinthu za ifase

Chiyambi

M'mapulogalamu azachipatala odwala nthawi zambiri amagwiritsa ntchito mankhwala angapo nthawi imodzi, ndipo mankhwalawa amathanso kubweretsa mankhwala - mankhwala osokoneza bongo (DDI) omwe ali ndi kuthekera koyambitsa matenda akulu kapena kusintha kwa chithandizo. Kuyeserera kwa DDI nthawi zambiri kumayamba ndi kuyesa kwa Vitro kuzindikira zomwe zingakhudze mawonekedwe osokoneza bongo a DDI ndikupeza magawo a kinetic kuti aphunzirenso. Ma enzymes osokoneza bongo akhala akuyang'ana koyamba kafukufuku wa DDI. M'zaka zaposachedwa, ndikukula kwa ukadaulo wa Soology Yachilengedwe, kupita patsogolo kofunikira kwachitika pakuwerengera mankhwala ku Vitro, ndipo kufunikira kwa kuwunika kwa Vitro Kuyika kwa ddis akukopa chidwi.

Zoyendera ndi maudindo awo

Transporter ikutanthauza mapuloteni omasulira mu cell nembanemba osiyanasiyana omwe amakaniza kulowa ndi kutuluka kwa mikhalidwe ya endo native membranes. Mu kusinthira mankhwala osokoneza bongo ndi mawu ogulitsa omwe amamwa mankhwala osokoneza bongo monga magawo a cell nembane kapena ziwalo, ndikugwira ntchito ya ma transmembrane mankhwala, makamaka kuphatikiza mabanja awiri: The ATP - Cassette (ABC)Superfamamily ndi solute wonyamula superfamily (SLC Kuyendetsa), komwe kumalamulira mankhwala osokoneza bongo.

ABC Kuyendetsandi atp - zonyamula zomwe zimayendetsa magawo osiyanasiyana (E.g., a ion, lipids, ndi mankhwala) kudutsa cell membranes, nthawi zambiri motsutsana ndi zinthu zosafunikira. Amasewera maudindo akuluakulu pokana mankhwala, kagayidwe kagayidwe kambiri, komanso detoxarnar.Kuyendetsa ZoyendetsaAmakhala sekondale yogwira kapena yothandizira omwe amakaniza kayendedwe ka ntchentche monga shuga, ma amino acid, ndi ma neurotransters. Mosiyana ndi ma abc oyendetsa a ABC, safuna atp mwachindunji koma amadalira ion gradels.

Kupititsa Patsambalo Mediate mankhwala makamaka P - Glycoprotein (P - Dera), Dera - Deran - Deran - Pulogalamu Yolimba (MDR1). Ndi mamembala a ATP - kumanga Cassette (ABC) kunyamula banja la hydrolyzed atp pakuyendetsa mankhwala ndi zinthu za Endogenous. Kuyendetsa omwe amakaniza kulowa kwa mankhwalawa kumatha kukwera malo osungirako za phala, makamaka osungirako anyezi (oterera), oyendetsa), ectic), enc.

Zoyendetsa Zofunikira ndi Maudindo Awo:

• -Bjop(Fungu mchere wotumiza mchere):Zovuta za Bile Acid mu chiwindi, BSEAP Dysfuction imalumikizidwa ndi matenda a chorestotic chiwindi. Mankhwala - Kusunthidwa - - Misapo ya BSEP imatha kuyambitsa hepatotocticity.
• -Bcrp(Khansa ya m'mawere pokana mapuloteni):BCRP imakhudza bioavailability wa mankhwala a chemotherapeutics ndi ma antiviral
• -Mate1 / Mate2 - K(Ma protein ootchera toxin):Ikupezeka mu impso ndi hepatic minote minofu, mate1 ndi mnzanga2 - k ntchentche mankhwala, amagwira ntchito yotsatsa.
• -Oatp1b1(Slco1b1):Kutsitsa chiwindi chotsimikizika chotsimikizika cha chitsimikizo cha statin. Oatp1b1 imagwira ntchito yofunika kwambiri yothetsera mavuto a Elirubic a acid, bilirubin, mahomoni ophatikizika, komanso mankhwala osokoneza bongo, komanso mankhwala osokoneza bongo.
• -Oat1(Slc22a6):Amasungunulira aimpso m'mbuyo wa akanema, kuphatikizapo ma antivarals ndi NSAIDs, amalimbikitsa chiopsezo cha nephrotoxicity.

Kutumiza Kutchire ndi DDI

Kuyendetsa Chopingandi gawo lofunikira la kukula kwa mankhwala. Cholepheretsa choletsa chimagwira ntchito yopatsa chidwi - Zogwirizana ndi Mankhwala (DDI) pokhudza mayamwidwe, kugawa, kagayidwe, ndi mawu a CO - Mankhwala othandizira. Zoletsa za Exlux zoyendetsa monga mdr1 (p - GP) ndi BCRP imatha kuchepetsa kuchotsedwa kwa ma cell mankhwalawa, omwe angakhale ndi vuto lalikulu la intracellular komanso dongosolo. Mofananamo, chopinga chopitilira zojambula ngati Oatp1b1 chitha kuchepa mphamvu mankhwala, pomwe bsefe, amatha kusokoneza bile acid dy Kuphatikiza apo, zonyamula ngati mate1, Meta2 - k, ndi oat1, ndizofunikira kwambiri kusinthira kwa impso mankhwala, pomwe zimalepheretsa kuwunika kwa mankhwala. Mu mitundu ya Vitro, kuphatikizaMdck IIndiCaco - 2Mizere yam'manja, imagwiritsidwa ntchito kwambiri kuwunika njira zosinthira izi, kupereka madera ofunikira mu chipewa cha DDI pokonzekera mankhwala.

Mu mitundu ya Vitro Yoyendetsa Maphunziro

Kumvetsetsa ntchito ndi kuneneratu zonyamula - DDIS yokhazikika imadalira mitundu yapadera. Ofufuza amagwiritsa ntchitoHek293 mockMaselo ngati akuwongolera, kuonetsetsa kuti mayendedwe aliwonse omwe amawona ali chifukwa cha zomwe zimabweretsa. Hek293 momasuka imapereka maziko osasinthasintha, pomwe hek293 mock imakhala pakatikati kuti igwirizane ndi zoyesa. Njira imodzi imagwiritsa ntchitonembanemba vesiclesKuchokera maselo okwera oyendetsa, nthawi zambiri amapatula ma cell a hek293. Mofananamo,KuseweretsaMitundu ndiyofunikira posiyanitsa mayendedwe osokoneza kuchokera ku chiwongola dzanja chokwanira. Mock SLC Kutumiza Chizindikiro kutsimikizira kuti kayendedwe ka gawo lapansi ndikunyamula - Kudalira, komanso kunyoza kuyesa kutsimikizira kudalirika kwa fanizoli. Njira yofananira iyi pogwiritsa ntchito hek293 mock ndi mock Sluck Storeer yathu imawonjezera luso lathu pophunzira ATP - Kutengera mayendedwe omwe amakhudzidwa ndi kagayidwe kam'madzi.

Caco - mzere wa cell, wochokera ku Carcinoma wamphamvu wa anthu, mtundu wina wapadera womwe umagwiritsidwa ntchito poyerekeza mayamwidwe mankhwala osokoneza bongo. Kutha kwake kusiyanitsa kulowa mu lowecyte - ma cell omwe akuwonetsa zosintha zosiyanasiyana zonyamula, monga p -

Kuphatikiza apo, kusuntha - Zithunzi Zosiyanasiyana ngati maselo owonetsera za BCRP kuthandizira kuti mupeze gawo lalikulu, machitidwe a ma coolter a mankhwala, ndi kuchuluka komwe kumasinthira zochitika zoyendera. Mukaphatikizidwa ndi deta kuchokera ku ma vesicular artays, ma cell a cell awapereka kuwunika kwathunthu mu Mphamvu Yoyendetsa - Mankhwala Osokoneza bongo.

Mapeto

Mwachidule, kumvetsetsa zosinthana ndi zomwe zimagwiritsa ntchito ndikofunikira kuti mutseke chitetezo cha mankhwala osokoneza bongo komanso kuchita bwino. Kupititsa patsogolo monga mdr1 (p - GP), BCRP, ndi BSEP pambali pa oatp 1B1 ndi oat1 slipter osinthira maudindo ofunikira mu mankhwala ama Pharmacokinetics. Kugwiritsa ntchito mitundu ya Vitro kuphatikiza ku MDCY II, Caco - maselo owonetsera a BCR1, ndipo mtundu wa anthu wa BRR1 umapereka njira zotchingira mankhwala ndi mankhwala osokoneza bongo komanso mankhwala osokoneza bongo. Kuzindikira kumeneku ndikofunikira kuti mutseke kugwiritsa ntchito mankhwala ndi chitetezo muzachipatala.