The 24 references with contexts in paper R. Kazakov E., V. Evteev A., O. Muslimova V., I. Mazerkina A., E. Demchenkova Yu., E. Shikh V., Р. Казаков Е., В. Евтеев А., О. Муслимова В., И. Мазеркина А., Е. Демченкова Ю., Е. Ших В. (2018) “Перспективы использования полиморфизма C3435T гена P-гликопротеина ABCB1 в персонализированной медицине // Prospects of using C3435T polymorphism in the ABCB1 gene encoding P-glycoprotein in personalised medicine” / spz:neicon:vedomostincesmp:y:2017:i:4:p:212-220

1
Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22(47): 7468–85.
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    Äâå ãîìîëîãè÷íûå äðóã äðóãó è ñèììåòðè÷íî ðàñïîëîæåííûå àìèíîêèñëîòíûå ïîñëåäîâàòåëüíîñòè ôîðìèðóþò ïî 6 òðàíñìåìáðàííûõ äîìåíîâ è ïî 1 äîìåíó ñ ÀÒÔàçíîé àêòèâíîñòüþ, ôîðìèðóÿ â ìåìáðàíå ïîðó (èç 12 òðàíñìåìáðàííûõ äîìåíîâ)
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    . Ïðè îáñëåäîâàíèè 247 ÷åëîâåê ðàçíîé ýòíè÷åñêîé ïðèíàäëåæíîñòè áûëè âûÿâëåíû 48 ïîëèìîðôèçìîâ ãåíà Ð-ãëèêîïðîòåèíàABCB1, 13 èç êîòîðûõ áûëè ñâÿçàíû ñ èçìåíåíèåì ïåðâè÷íîé ñòðóêòóðû [2]. Íà ðèñóíêå 1 ïîêàçàíû ìåñòà íàèáîëåå ðàñïðîñòðàíåííûõ çàìåí.

2
Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype structure in the humanABCB1(MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13(8): 481–94.
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    äðóã äðóãó è ñèììåòðè÷íî ðàñïîëîæåííûå àìèíîêèñëîòíûå ïîñëåäîâàòåëüíîñòè ôîðìèðóþò ïî 6 òðàíñìåìáðàííûõ äîìåíîâ è ïî 1 äîìåíó ñ ÀÒÔàçíîé àêòèâíîñòüþ, ôîðìèðóÿ â ìåìáðàíå ïîðó (èç 12 òðàíñìåìáðàííûõ äîìåíîâ) [1]. Ïðè îáñëåäîâàíèè 247 ÷åëîâåê ðàçíîé ýòíè÷åñêîé ïðèíàäëåæíîñòè áûëè âûÿâëåíû 48 ïîëèìîðôèçìîâ ãåíà Ð-ãëèêîïðîòåèíàABCB1, 13 èç êîòîðûõ áûëè ñâÿçàíû ñ èçìåíåíèåì ïåðâè÷íîé ñòðóêòóðû
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    . Íà ðèñóíêå 1 ïîêàçàíû ìåñòà íàèáîëåå ðàñïðîñòðàíåííûõ çàìåí. Ïðåäñòàâëåííûå äàííûå ñâèäåòåëüñòâóþò î òîì, ÷òî îáû÷íî îíè ëîêàëèçîâàíû â öèòîïëàçìàòè÷åñêîì ïðîñòðàíñòâå è ìîãóò âëèÿòü íà ñóáñòðàòíóþ ñïåöèôè÷íîñòü òðàíñïîðòåðà, êàê ïðàâèëî, â ñòîðîíó ñíèæåíèÿ ñêîðîñòè åãî óäàëåíèÿ èç êëåòêè è/èëè îðãàíèçìà.

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    Ïðè ýòîì ñîäåðæàíèå Ð-ãëèêîïðîòåèíà â äâåíàäöàòèïåðñòíîé êèøêå ó ëèö ñ ãåíîòèïîì 3435ÒÒ áûëî â 2 ðàçà ìåíüøå, ÷åì ó ãîìîçèãîò 3435ÑÑ.  äàëüíåéøåì âëèÿíèþ ïîëèìîðôèçìà ãåíà ABCB1íà ôàðìàêîêèíåòèêó äèãîêñèíà áûëî ïîñâÿÒàáëèöà 1 ×ÀÑÒÎÒÛ ÀËËÅËÅÉ ÃÅÍÀABCB1Ó ÏÐÅÄÑÒÀÂÈÒÅËÅÉ ÐÀÇËÈ×ÍÛÕ ÐÀÑ
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    Ïîëîæåíèå çàìåíû â ÄÍÊÓ÷àñòîê ãåíà Íóêëåîòèäíàÿ çàìåíà Àìèíîêèñëîòíàÿ çàìåíà* ×àñòîòà ìèíîðíîãî àëëåëÿ ÅâðîïåîèäûÍåãðîèäûÌîíãîëîèäû (–274)èíòðîí –1G > A—00,0160 (–60)èíòðîí –1A > T—00,0100 (–41)èíòðîí –1A > G—000,017 –241íåêîä. îáë.

3
Takane H, Kobayashi D, Hirota T, Kigawa J, Terakawa N, Otsubo K, et al. Haplotype-oriented genetic analysis and functional assessment of promoter variants in theMDR1(ABCB1) gene. J Pharmacol Exp Ther. 2004; 311(3): 1179–87.
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    Èçâåñòíî, ÷òî àêòèâèðîâàòü òðàíñêðèïöèþ ãåíàABCB1ñïîñîáíû íåêîòîðûå ñòðåññîâûå àãåíòû: òåïëîâîé øîê, ÷àñòè÷íàÿ ðåçåêöèÿ ïå÷åíè, âîçäåéñòâèå êàíöåðîãåíîâ, õèìèîòåðàïåâòè÷åñêèå ïðåïàðàòû, óëüòðàôèîëåòîâîå è ðåíòãåíîâñêîå èçëó÷åíèå,àâïðîìîòîðå ãåíà èìååòñÿ íåñêîëüêî ïîñëåäîâàòåëüíîñòåé äëÿ ñâÿçûâàíèÿ ôàêòîðîâ òåïëîâîãî øîêà
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    . Ñâåäåíèÿ î ÷àñòîòàõ íàèáîëåå ðàñïðîñòðàíåííûõ àëëåëåé ãåíàABCB1îáîáùåíû â òàáëèöå 1.  ôàðìàêîãåíåòè÷åñêèõ èññëåäîâàíèÿõ íàèáîëüøåå ÷èñëî ðàáîò ïîñâÿùåíî êëèíè÷åñêîé çíà÷èìîñòè òðåõ ïîëèìîðôèçìîâ: C1236T, G2677T/A è C3435T, èç êîòîðûõ òîëüêî îäèí, G2677T/A, ñâÿçàí ñ èçìåíåíèåì ñòðóêòóðû ãëèêîïðîòåèíà.

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Romanov BK. Regulation of myocardial lysosomal enzyme activity by calcium. Biomedical Chemistry 2005; 51(6): 634–42 (in Russian).
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    Àññîöèàöèÿ ïîëèìîðôèçìà C3435T ãåíàABCB1 ñ ðàçâèòèåì íåæåëàòåëüíûõ ëåêàðñòâåííûõ ðåàêöèé Äèãîêñèí Äèãîêñèí — ýòî ñåðäå÷íûé ãëèêîçèä, øèðîêî ïðèìåíÿþùèéñÿ â êëèíè÷åñêîé ïðàêòèêå äëÿ íîðìàëèçàöèè ñåðäå÷íîãî ðèòìà ïðè ïîñòîÿííîé ôîðìå ôèáðèëëÿöèè ïðåäñåðäèé
    Exact
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    . Ñîâìåñòíîå ïðèìåíåíèå ñ äèãîêñèíîì ËÑ, èíãèáèðóþùèõ Ð-ãëèêîïðîòåèí, íàïðèìåð, êëàðèòðîìèöèíà, õèíèäèíà èëè öèêëîñïîðèíà, ïðèâîäèò ê çíà÷èòåëüíîìó ïîâûøåíèþ êîíöåíòðàöèè äèãîêñèíà â ïëàçìå êðîâè, à ïðèåì ñîâìåñòíî ñ äèãîêñèíîì èíäóêòîðîâ Ð-ãëèêîïðîòåèíà (íàïðèìåð, ðèôàìïèöèíà), íàïðîòèâ, ïðèâîäèò ê ñíèæåíèþ óðîâíÿ äèãîêñèíà [5].

5
Li Y, Wang Y, Sun J, Li Y, Yang L. Distribution of the functionalMDR1 C3435T polymorphism in the Han population of China. Swiss Med Wkly. 2006; 136(23–24): 377–82.
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    Ñîâìåñòíîå ïðèìåíåíèå ñ äèãîêñèíîì ËÑ, èíãèáèðóþùèõ Ð-ãëèêîïðîòåèí, íàïðèìåð, êëàðèòðîìèöèíà, õèíèäèíà èëè öèêëîñïîðèíà, ïðèâîäèò ê çíà÷èòåëüíîìó ïîâûøåíèþ êîíöåíòðàöèè äèãîêñèíà â ïëàçìå êðîâè, à ïðèåì ñîâìåñòíî ñ äèãîêñèíîì èíäóêòîðîâ Ð-ãëèêîïðîòåèíà (íàïðèìåð, ðèôàìïèöèíà), íàïðîòèâ, ïðèâîäèò ê ñíèæåíèþ óðîâíÿ äèãîêñèíà
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    . Êðîìå òîãî, äèãîêñèí îïîñðåäîâàííî, ÷åðåç ðåöåïòîðû ñòåðîèäíûõ êñåíîáèîòèêîâ, óâåëè÷èâàåò óðîâåíü ýêñïðåññèè ãåíà Ð-ãëèêîïðîòåèíà [6].  2000 ã. áûëà îïóáëèêîâàíà ñòàòüÿ Hoffmeyer S. è ñîàâò., â êîòîðîé áûëè èçëîæåíû ðåçóëüòàòû ïåðâîãî èçó÷åíèÿ âçàèìîñâÿçè ïîëèìîðôèçìà ãåíàABCB1 ñ ôàðìàêîêèíåòèêîé äèãîêñèíà [7].

6
Takara K, Takagi K, Tsujimoto M, Ohnishi N, Yokoyama T. Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneouslydown-regulatessteroidxenobioticreceptor mRNA. Biochem Biophys Res Commun. 2003; 306(1): 116–20.
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    íàïðèìåð, êëàðèòðîìèöèíà, õèíèäèíà èëè öèêëîñïîðèíà, ïðèâîäèò ê çíà÷èòåëüíîìó ïîâûøåíèþ êîíöåíòðàöèè äèãîêñèíà â ïëàçìå êðîâè, à ïðèåì ñîâìåñòíî ñ äèãîêñèíîì èíäóêòîðîâ Ð-ãëèêîïðîòåèíà (íàïðèìåð, ðèôàìïèöèíà), íàïðîòèâ, ïðèâîäèò ê ñíèæåíèþ óðîâíÿ äèãîêñèíà [5]. Êðîìå òîãî, äèãîêñèí îïîñðåäîâàííî, ÷åðåç ðåöåïòîðû ñòåðîèäíûõ êñåíîáèîòèêîâ, óâåëè÷èâàåò óðîâåíü ýêñïðåññèè ãåíà Ð-ãëèêîïðîòåèíà
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    .  2000 ã. áûëà îïóáëèêîâàíà ñòàòüÿ Hoffmeyer S. è ñîàâò., â êîòîðîé áûëè èçëîæåíû ðåçóëüòàòû ïåðâîãî èçó÷åíèÿ âçàèìîñâÿçè ïîëèìîðôèçìà ãåíàABCB1 ñ ôàðìàêîêèíåòèêîé äèãîêñèíà [7]. Ïðîàíàëèçèðîâàâ 15 ïîëèìîðôíûõ ìàðêåðîâ, àâòîðû îáíàðóæèëè, ÷òîÑmaxäèãîêñèíà ó ëèö ñ ãåíîòèïîì 3435ÒÒ â ïëàçìå êðîâè íà 38 % âûøå, ÷åì ó ëèö ñ ãåíîòèïîì 3435ÑÑ.

7
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97(7): 3473–8.
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    Êðîìå òîãî, äèãîêñèí îïîñðåäîâàííî, ÷åðåç ðåöåïòîðû ñòåðîèäíûõ êñåíîáèîòèêîâ, óâåëè÷èâàåò óðîâåíü ýêñïðåññèè ãåíà Ð-ãëèêîïðîòåèíà [6].  2000 ã. áûëà îïóáëèêîâàíà ñòàòüÿ Hoffmeyer S. è ñîàâò., â êîòîðîé áûëè èçëîæåíû ðåçóëüòàòû ïåðâîãî èçó÷åíèÿ âçàèìîñâÿçè ïîëèìîðôèçìà ãåíàABCB1 ñ ôàðìàêîêèíåòèêîé äèãîêñèíà
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    . Ïðîàíàëèçèðîâàâ 15 ïîëèìîðôíûõ ìàðêåðîâ, àâòîðû îáíàðóæèëè, ÷òîÑmaxäèãîêñèíà ó ëèö ñ ãåíîòèïîì 3435ÒÒ â ïëàçìå êðîâè íà 38 % âûøå, ÷åì ó ëèö ñ ãåíîòèïîì 3435ÑÑ. Ïðè ýòîì ñîäåðæàíèå Ð-ãëèêîïðîòåèíà â äâåíàäöàòèïåðñòíîé êèøêå ó ëèö ñ ãåíîòèïîì 3435ÒÒ áûëî â 2 ðàçà ìåíüøå, ÷åì ó ãîìîçèãîò 3435ÑÑ.

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Chowbay B, Li H, David M, Cheung YB, Lee EJ. Meta-analysis of the influence ofMDR1C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol. 2005; 60(2): 159–71.
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    ïî ìíåíèþ àâòîðîâ îäíîãî èç ìåòà-àíàëèçîâ, íåñìîòðÿ íà äîñòîâåðíûå ðàçëè÷èÿ ïîêàçàòåëåéÑmaxèAUCïðè ïðèìåíåíèè äèãîêñèíà, íàëè÷èå àññîöèàöèè ïîëèìîðôèçìà Ñ3435Ò ñ ôàðìàêîêèíåòè÷åñêèìè ïîêàçàòåëÿìè è ýêñïðåññèåé P-ãëèêîïðîòåèíà ïîäòâåðæäåíî íå áûëî, è áûëî ïðåäëîæåíî â äàëüíåéøåì ñîñðåäîòî÷èòüñÿ íå íà àíàëèçå îäèíî÷íîãî ïîëèìîðôèçìà, à íà ó÷åòå èõ ñóììàðíîãî âëèÿíèÿ â ñîñòàâå ãàïëîòèïîâ
    Exact
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    . Òåì íå ìåíåå, ñîãëàñíî ïðîâåäåííîìó â Ðîññèè èññëåäîâàíèþ, áûëî îáíàðóæåíî êàê íàðàñòàíèå óðîâíÿ äèãîêñèíà â ïëàçìå êðîâè â ðÿäó 3435ÑÑ – 3435ÑÒ – 3435ÒÒ, òàê è óâåëè÷åíèå â ýòîì ðÿäó ñèìïòîìîâ ãëèêîçèäíîé èíòîêñèêàöèè.

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Sychev DA, Ignatiev IV, Andreev DA, Poshukaeva LG, Kolkhir PV, Zhukova EE, et al. Glycoprotein P pharmacogenetic assessment role in digoxin pharmacotherapy individualization: a new approach for an old problem. Russian Journal of Cardiology 2006; (4): 64–8 (in Russian).
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    À. è ñîàâò. áûë ïðåäëîæåí àëãîðèòì äîçèðîâàíèÿ äèãîêñèíà, ñîãëàñíî êîòîðîìó ó ïàöèåíòîâ ñ ãåíîòèïîì 3435ÒÒ íåîáõîäèìî íà÷èíàòü ëå÷åíèå ñ ïîëîâèíû òåðàïåâòè÷åñêîé äîçû (1,125 ìã/ñóò) ïðè ìîíèòîðèíãå êîíöåíòðàöèè äèãîêñèíà â ïëàçìå êðîâè ïàöèåíòà âî èçáåæàíèå äèãèòàëèñíîé èíòîêñèêàöèè
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    . Ôåêñîôåíàäèí Ôåêñîôåíàäèí, àíòàãîíèñò Í1-ãèñòàìèíîâûõ ðåöåïòîðîâ III ïîêîëåíèÿ, íå îêàçûâàþùèé ñåäàòèâíîãî ýôôåêòà íà ÖÍÑ, èñïîëüçóåòñÿ â ìåäèöèíñêîé Ãðóïïà ËÑÑóáñòðàòÐ-ãëèêîïðîòåèíà Äîïîëíèòåëüíîå âëèÿíèå íà Ð-ãëèêîïðîòåèí Ïðîòèâîîïóõîëåâûå Äàêòèíîìèöèí—* Äàóíîðóáèöèí— Äîêñîðóáèöèí— Èðèíîòåêàí— Ìèòîìèöèí— Äîöåòàêñåë— Ýïèðóáèöèí— Ýòîïîçèä— Ìèòîìèöèí— Ìèòîêñàíòðîí— Ïàêëèòàêñåë— Òàìîêñèôåí— Òåíèïî

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Drozdzik M, Rudas T, Pawlik A, Kurzawski M, Czerny B, Gornik W, et al. The effect of 3435C>TMDR1gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur J Clin Pharmacol. 2006; 62(11): 933–7.
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    Èçâåñòíî, ÷òî êåòîêîíàçîë ñ ýðèòðîìèöèíîì, èíãèáèðóþùèå P-ãëèêîïðîòåèí, âûçûâàþò ïðè ñîâìåñòíîì ïðèåìå óâåëè÷åíèå ñîäåðæàíèÿ ôåêñîôåíàäèíà â ïëàçìå êðîâè íà 64 è 9 % ñîîòâåòñòâåííî, à èíäóêòîð P-ãëèêîïðîòåèíà ðèôàìïèöèí âûçûâàåò îáðàòíûé ýôôåêò
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    . Ýòè íàáëþäåíèÿ ïîçâîëÿþò êîñâåííî îöåíèòü âêëàä Ð-ãëèêîïðîòåèíà â áèîäîñòóïíîñòü ôåêñîôåíàäèíà. Èçâåñòíî, ÷òî ôåêñîôåíàäèí ïðàêòè÷åñêè íå ïîäâåðãàåòñÿ áèîòðàíñôîðìàöèè, è ðîëü Ð-ãëèêîïðîòåèíà â åãî âûâåäåíèè ÿâëÿåòñÿ îñíîâîïîëàãàþùåé.

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Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U, et al.MDR1gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol. 2002; 53(5): 526–34.
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    Ñâåäåíèÿ î âëèÿíèè ïîëèìîðôèçìà ãåíàABCB1 íà ôàðìàêîêèíåòèêó ôåêñîôåíàäèíà íåìíîãî÷èñëåííû è äîâîëüíî ïðîòèâîðå÷èâû.  2002 ã. áûëè îïóáëèêîâàíû ðåçóëüòàòû èññëåäîâàíèÿ, íàïðàâëåííîãî íà óñòàíîâëåíèå âçàèìîñâÿçè ôàðìàêîêèíåòèêè ôåêñîôåíàäèíà ñ ïîëèìîðôíûì ìàðêåðîì Ñ3435Ò ãåíàABCB1
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    . Ñðåäè äîáðîâîëüöåâ íåìåöêîé íàöèíàëüíîñòè îòáèðàëèñü 10 íîñèòåëåé ãåíîòèïà 3435ÒÒ è ñòîëüêî æå íîñèòåëåé ãåíîòèïà 3435ÑÑ. Êðîìå ïîëèìîðôèçìà Ñ3435Ò, â ðàáîòå òàêæå îïðåäåëÿëè àëëåëè âîñüìè äðóãèõ ïîëèìîðôíûõ ìàðêåðîâ ãåíàABCB1.

12
Yi SY, Hong KS, Lim HS, Chung JY, Oh DS, Kim JR, et al. A variant 2677A allele of theMDR1gene affects fexofenadine disposition. Clin Pharmacol Ther. 2004; 76(5): 418–27.
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    Áûëî óñòàíîâëåíî, ÷òî àêòèâíîñòü P-ãëèêîïðîòåèíà â ëåéêîöèòàõ íîñèòåëåé ãåíîòèïà 3435ÒÒ íèæå, ïî ñðàâíåíèþ ñ íîñèòåëÿìè ãåíîòèïà 3435ÑÑ, îäíàêî äîñòîâåðíûõ ðàçëè÷èé ìåæäó âûáðàííûìè ãðóïïàìè ïî ôàðìàêîêèíåòè÷åñêèì ïîêàçàòåëÿì ôåêñîôåíàäèíà îáíàðóæåíî íå áûëî. Âïîñëåäñòâèè áûëà îïóáëèêîâàíà ðàáîòà êîðåéñêèõ àâòîðîâ, ïðîâåäåííàÿ íà 33 äîáðîâîëüöàõ êîðåéñêîé íàöèîíàëüíîñòè
    Exact
    [12]
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    . Äîáðîâîëüöû ïðèíèìàëè ïåðîðàëüíî ðàçîâóþ äîçó (180 ìã) ôåêñîôåíàäèíà, ïîñëå ÷åãî ó íèõ áûëè ïðîâåäåíû èçìåðåíèÿ ôàðìàêîêèíåòè÷åñêèõ ïàðàìåòðîâ. Èññëåäîâàòåëè îáíàðóæèëè, ÷òî ôàðìàêîêèíåòè÷åñêèå ïàðàìåòðû AUC0–24 ÷èÑmaxáûëè äîñòîâåðíî âûøå ó íîñèòåëåé ãåíîòèïà 3435ÒÒ, ïî ñðàâíåíèþ ñ 3435ÑÑ.

13
Goreva OB, Grishanova AY, Mukhin OV, Domnikova NP, Lyakhovich VV. Possible prediction of the efficiency of chemotherapy in patients with lymphoproliferative diseases based onMDR1gene G2677T and C3435T polymorphisms. Bull Exp Biol Med. 2003; 136(2): 183–5.
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    Ýôôåêòèâíîñòü õèìèîòåðàïèè  2003 ã. â Íîâîñèáèðñêå áûë ïðîâåäåí ãåíåòè÷åñêèé àíàëèç äâóõ ïîëèìîðôíûõ ìàðêåðîâ, G2677Ò è Ñ3435Ò, ñðåäè åâðîïåîèäîâ Çàïàäíîé Ñèáèðè, çäîðîâûõ äîáðîâîëüöåâ è ïàöèåíòîâ ñ ëèìôîïðîëèôåðàòèâíûìè çàáîëåâàíèÿìè
    Exact
    [13]
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    . Ìåæäó ãðóïïàìè íå áûëî óñòàíîâëåíî äîñòîâåðíûõ ðàçëè÷èé ïî ãåíîòèïàì ïîëèìîðôíûõ ìàðêåðîâ ãåíàABCB1. Ïðè ýòîì àâòîðû îáíàðóæèëè ñâÿçü ìåæäó ãåíîòèïîìABCB1è ðåçèñòåíòíîñòüþ ê õèìèîòåðàïèè. Òàê, ðåçèñòåíòíîñòü ó ïàöèåíòîâ, ãîìîçèãîòíûõ ïî ãàïëîòèïó 2677ÒҖ3435ÒÒ áûëà â 17 ðàç âûøå, ÷åì ó ïàöèåíòî⠗ íîñèòåëåé ãàïëîòèïà 2677GG–3435ÑÑ.

14
Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, et al. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of theABCB1(MDR1) gene. Transplantation 2002; 74(4): 571–2.
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    Èììóíîñóïðåññîðû Èììóíîñóïðåññîðû (èììóíîäåïðåññàíòû) ïðèìåíÿþòñÿ ñ öåëüþ ïðåäîòâðàùåíèÿ îòòîðæåíèÿ ïåðåñàæåííîãî îðãàíà èëè òêàíè. Ñ ýòîé öåëüþ ðàçðàáîòàí öåëûé ðÿä ËÑ, îêàçûâàþùèõ èììóíîñóïðåññîðíîå âîçäåéñòâèå: öèêëîñïîðèí, òàêðîëèìóñ, ñèðîëèìóñ è äð.
    Exact
    [14]
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    . Áîëüøèíñòâî èììóíîñóïðåññîðîâ ÿâëÿþòñÿ ñóáñòðàòàìè Ð-ãëèêîïðîòåèíà. Äàííûå ËÑ õàðàêòåðèçóþòñÿ óçêèì òåðàïåâòè÷åñêèì îêíîì, îáëàäàþò äîâîëüíî íèçêîé áèîäîñòóïíîñòüþ ïðè ïåðîðàëüíîì ïðèìåíåíèè è áîëüøèì ðàçáðîñîì â îòíîøåíèè èíäèâèäóàëüíûõ ôàðìàêîêèíåòè÷åñêèõ ïàðàìåòðîâ.

15
Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K, et al. C3435T polymorphism in theMDR1gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 2002; 12(6): 451–7.
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    — Èíãèáèòîðû ÂÈ×-ïðîòåàçû Àìïðåíàâèð— Èíäèíàâèð— Íåëôèíàâèð— Ñàíêâèíàâèð— Ðèòèíàâèð— Ãèïîëèïèäåìè÷åñêèå Àòîðâàñòàòèíèíãèáèðóåò Ëîâàñòàòèí— Áëîêàòîðû ìåäëåííûõ êàëüöèåâûõ êàíàëîâ Äèëòèàçåì— Âåðàïàìèëèíãèáèðóåò Äðóãèå ãðóïïû ËÑ Ýñòðàäèîë— Êîëõèöèí— Äåáðèçîõèí— Ýìåòèí— Ôåíèòîèí— Òàáëèöà 2 ÑÏÈÑÎÊ ÍÀÈÁÎËÅÅ ÈÇÂÅÑÒÍÛÕ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒÂ,  ÂÛÂÅÄÅÍÈÈ ÊÎÒÎÐÛÕ ÈÇ ÎÐÃÀÍÈÇÌÀ Ó×ÀÑÒÂÓÅÒ Ð-ÃËÈÊÎÏÐÎÒÅÈÍ
    Exact
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    * Ïðî÷åðê â äàííîé ãðàôå îçíà÷àåò, ÷òî ñóùåñòâåííîãî âëèÿíèÿ äàííûé ñóáñòðàò íà àêòèâíîñòü Ð-ãëèêîïðîòåèíà íå îêàçûâàåò ïðàêòèêå ïðè ñåçîííûõ àëëåðãè÷åñêèõ ðèíèòàõ è ïðè õðîíè÷åñêîé èäèîïàòè÷åñêîé êðàïèâíèöå.

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    Ïåðåäîçèðîâêà òàêðîëèìóñà ïðèâîäèò ê ãèïåðòåíçèè, ãèïåðãëèêåìèè è íåôðîïàòèè. Òàêèì îáðàçîì, ïðè èñïîëüçîâàíèè èììóíîñóïðåññîðîâ íåîáõîäèì ñòðîãèé ìîíèòîðèíã èõ ðàâíîâåñíîé êîíöåíòðàöèè äëÿ ïðåäîòâðàùåíèÿ íåæåëàòåëüíûõ ðåàêöèé
    Exact
    [15]
    Suffix
    . Äàííûå ËÑ íå òîëüêî ÿâëÿþòñÿ ñóáñòðàòàìè Ð-ãëèêîïðîòåèíà, îíè òàêæå ñïîñîáíû ìîäèôèöèðîâàòü åãî àêòèâíîñòü [16]. Áîëüøèíñòâî àâòîðîâ ñõîäÿòñÿ âî ìíåíèè, ÷òî â ñëó÷àå èììóíîäåïðåññàíòîâ íàáëþäàåòñÿ ñîâìåñòíàÿ ðàáîòà Ð-ãëèêîïðîòåèíà ñ öèòîõðîìàìè CYP3A-ñåìåéñòâà, â ðåçóëüòàòå ÷åãî îáðàçóåòñÿ ñâîåîáðàçíûé «àáñîðáòèâíûé áàðüåð», êîíòðîëèðóþùèé áèîäîñòóïíîñòü ñîîòâåòñòâóþùèõ ËÑ [15].

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    Áîëüøèíñòâî àâòîðîâ ñõîäÿòñÿ âî ìíåíèè, ÷òî â ñëó÷àå èììóíîäåïðåññàíòîâ íàáëþäàåòñÿ ñîâìåñòíàÿ ðàáîòà Ð-ãëèêîïðîòåèíà ñ öèòîõðîìàìè CYP3A-ñåìåéñòâà, â ðåçóëüòàòå ÷åãî îáðàçóåòñÿ ñâîåîáðàçíûé «àáñîðáòèâíûé áàðüåð», êîíòðîëèðóþùèé áèîäîñòóïíîñòü ñîîòâåòñòâóþùèõ ËÑ
    Exact
    [15]
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    . Ïðè ýòîì ïðèðîäà èõ âçàèìîäåéñòâèÿ íå ñîâñåì ÿñíà: ïðîèñõîäèò ëè êîíòàêò íà óðîâíå ñàìèõ ãåíîâ, èëè æå íà óðîâíå èõ ïðîäóêòîâ. Ëîïåðàìèä Ëîïåðàìèä — ëåêàðñòâåííîå ñðåäñòâî, âîçáóæäàþùåå îïèîèäíûå ðåöåïòîðû ãëàäêèõ ìûøö êèøå÷íèêà, ïðèìåíÿåòñÿ ïðè ëå÷åíèè îñòðîé è õðîíè÷åñêîé äèàðåè.

16
Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1(P-glycoprotein): Recent advances and clinical relevance. Clin Pharmacol Ther. 2004; 75(1): 13–33.
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    Òàêèì îáðàçîì, ïðè èñïîëüçîâàíèè èììóíîñóïðåññîðîâ íåîáõîäèì ñòðîãèé ìîíèòîðèíã èõ ðàâíîâåñíîé êîíöåíòðàöèè äëÿ ïðåäîòâðàùåíèÿ íåæåëàòåëüíûõ ðåàêöèé [15]. Äàííûå ËÑ íå òîëüêî ÿâëÿþòñÿ ñóáñòðàòàìè Ð-ãëèêîïðîòåèíà, îíè òàêæå ñïîñîáíû ìîäèôèöèðîâàòü åãî àêòèâíîñòü
    Exact
    [16]
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    . Áîëüøèíñòâî àâòîðîâ ñõîäÿòñÿ âî ìíåíèè, ÷òî â ñëó÷àå èììóíîäåïðåññàíòîâ íàáëþäàåòñÿ ñîâìåñòíàÿ ðàáîòà Ð-ãëèêîïðîòåèíà ñ öèòîõðîìàìè CYP3A-ñåìåéñòâà, â ðåçóëüòàòå ÷åãî îáðàçóåòñÿ ñâîåîáðàçíûé «àáñîðáòèâíûé áàðüåð», êîíòðîëèðóþùèé áèîäîñòóïíîñòü ñîîòâåòñòâóþùèõ ËÑ [15].

17
Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, et al. Effects ofABCB1(multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 2003; 13(11): 651–60.
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    Òàê, â èññëåäîâàíèè, ïðîâåäåííîì íà äîáðîâîëüöàõ, áûëî óñòàíîâëåíî, ÷òî ïðè ïðèìåíåíèè ëîïåðàìèäà ó ëèö ñ ãîìîçèãîòíûì ãåíîòèïîì 3435ÒÒ ãåíàABCB1äîñòèãàåòñÿ äîñòîâåðíî áîëåå âûñîêàÿCmax,÷åìóëèöñãåíîòèïàìè 3435ÑÒ è 3435ÑÑ
    Exact
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    . Îäíàêî íàëè÷èå òàêîé àññîöèàöèè îïðîâåðãàåòñÿ äðóãèìè êîëëåêòèâàìè èññëåäîâàòåëåé [18]. Àìëîäèïèí Àìëîäèïèí, áëîêàòîð ìåäëåííûõ êàëüöèåâûõ êàíàëîâ III ïîêîëåíèÿ, ïðèìåíÿåòñÿ ïðè àðòåðèàëüíîé ãèïåðòåíçèè, ñòàáèëüíîé ñòåíîêàðäèè íàïðÿæåíèÿ è ñòåíîêàðäèè Ïðèíöìåòàëà â âèäå ìîíîòåðàïèè ëèáî â êîìáèíàöèè ñ äðóãèìè àíòèãèïåðòåíçèâíûìè èëè àíòèàíãèíàëüíûìè ñðåäñòâàìè.

18
Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL. No effect of MDR1C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther. 2003; 74(5): 487–98.
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    Òàê, â èññëåäîâàíèè, ïðîâåäåííîì íà äîáðîâîëüöàõ, áûëî óñòàíîâëåíî, ÷òî ïðè ïðèìåíåíèè ëîïåðàìèäà ó ëèö ñ ãîìîçèãîòíûì ãåíîòèïîì 3435ÒÒ ãåíàABCB1äîñòèãàåòñÿ äîñòîâåðíî áîëåå âûñîêàÿCmax,÷åìóëèöñãåíîòèïàìè 3435ÑÒ è 3435ÑÑ [17]. Îäíàêî íàëè÷èå òàêîé àññîöèàöèè îïðîâåðãàåòñÿ äðóãèìè êîëëåêòèâàìè èññëåäîâàòåëåé
    Exact
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    . Àìëîäèïèí Àìëîäèïèí, áëîêàòîð ìåäëåííûõ êàëüöèåâûõ êàíàëîâ III ïîêîëåíèÿ, ïðèìåíÿåòñÿ ïðè àðòåðèàëüíîé ãèïåðòåíçèè, ñòàáèëüíîé ñòåíîêàðäèè íàïðÿæåíèÿ è ñòåíîêàðäèè Ïðèíöìåòàëà â âèäå ìîíîòåðàïèè ëèáî â êîìáèíàöèè ñ äðóãèìè àíòèãèïåðòåíçèâíûìè èëè àíòèàíãèíàëüíûìè ñðåäñòâàìè.

19
Kim KA, Park PW, Park JY. Effect ofABCB1(MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br J Clin Pharmacol. 2007; 63(1): 53–8.
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     2007 ã. êîðåéñêèìè èññëåäîâàòåëÿìè íà 26 çäîðîâûõ äîáðîâîëüöàõ áûëî ïîêàçàíî, ÷òî òàêàÿ àññîöèàöèÿ èìååòñÿ, ïðè÷åì ïàðîäîêñàëüíàÿ: ó ãîìîçèãîò ñ «íîðìàëüíûì »ãåíîòèïîì (2677GG/3435ÑÑ, îáà ïîëèìîðôíûõ ìàðêåðà áûëè ñöåïëåíû) âûâåäåíèå àìëîäèïèíà áûëî äîñòîâåðíî íèæå (âûøå çíà÷åíèÿ Ñmax,AUC, ìåíüøåÒmax, è ò.ä.)
    Exact
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    . Ñõîäíûå ðåçóëüòàòû áûëè ïîëó÷åíû êèòàéñêèìè èññëåäîâàòåëÿìè íà ïîæèëûõ ïàöèåíòàõ ñ ýññåíöèàëüíîé ãèïåðòåíçèåé: íîñèòåëè ãåíîòèïà 3435ÒÒ ãåíàABCB1îòëè÷àþòñÿ ïîâûøåííûì êëèðåíñîì (â 1,5 ðàçà), ïî ñðàâíåíèþ ñ íîñèòåëÿìè äðóãèõ ãåíîòèïîâ [20].

20
Zuo XC, Zhang WL, Yuan H, Barrett JS, Hua Y, Huang ZJ, et al.ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis. Drug Metab Pharmacokinet. 2014; 29(4): 305–11.
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    Ñõîäíûå ðåçóëüòàòû áûëè ïîëó÷åíû êèòàéñêèìè èññëåäîâàòåëÿìè íà ïîæèëûõ ïàöèåíòàõ ñ ýññåíöèàëüíîé ãèïåðòåíçèåé: íîñèòåëè ãåíîòèïà 3435ÒÒ ãåíàABCB1îòëè÷àþòñÿ ïîâûøåííûì êëèðåíñîì (â 1,5 ðàçà), ïî ñðàâíåíèþ ñ íîñèòåëÿìè äðóãèõ ãåíîòèïîâ
    Exact
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    . Àâòîðû îáúÿñíÿþò ýòîò ôàêò òåì, ÷òî ïîëèìîðôèçì, ïðèâîäÿùèé ê ñíèæåíèþ ýêñïðåññèè Ð-ãëèêîïðîòåèíà, ñïîñîáñòâóåò âûâåäåíèþ åãî ñóáñòðàòà ñëåäóþùèì îáðàçîì: èíäèâèäóóìû, ó êîòîðûõ Ð-ãëèêîïðîòåèí ðàáîòàåò ïðèíöèïèàëüíî õóæå, ìîãóò êîìïåíñèðîâàòü åãî íåõâàòêó çà ñ÷åò ïîñòîÿííî àêòèâèðîâàííîãî ìèêðîñîìàëüíîãî îêèñëåíèÿ, âêëþ÷àÿ, ïðåæäå âñåãî, öèòîõðîìû Ð-450 3À.

21
Semenov AV, Sychev DA, Kukes VG. Effect of genesSLCO1B1and MDR1polymorphism on atorvastatin pharmacokinetics and pharmacodynamics in patients with primary hypercholesterolemia: results of pilot pharmacogenetics study. Rational Pharmacother Card. 2008; (2): 47–50 (in Russian).
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    Òåì íå ìåíåå, â ðåçóëüòàòå ïðîâåäåííîé ðàáîòû áûëî ïîêàçàíî, ÷òî, íåñìîòðÿ íà áîëüøîé òåîðåòè÷åñêèé èíòåðåñ, ïîëèìîðôèçì ãåíàABCB1âëèÿåò íà èíäèâèäóàëüíûå îñîáåííîñòè âûâåäåíèÿ àìëîäèïèíà, íî íå íà åãî àíòèãèïåðòåíçèâíóþ ýôôåêòèâíîñòü. Ñòàòèíû Âëèÿíèå ïîëèìîðôèçìà Ñ3435Ò ãåíàABCB1 íà ýôôåêòèâíîñòü è áåçîïàñíîñòü ïðèìåíåíèÿ ñòàòèíîâ ÿâëÿëîñü îáëàñòüþ èíòåðåñîâ ìíîãèõ èññëåäîâàòåëåé
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    .  2015 ã. êîëëåêòèâîì àâòîðîâ áûëè îïóáëèêîâàíû ðåçóëüòàòû ìåòà-àíàëèçà, îáîáùàþùèå îïûò ìíîãîëåòíèõ èññëåäîâàíèé ïîëèìîðôèçìà ãåíàABCB1 [22]. Ñðåäè 140 èññëåäîâàíèé áûëî îòîáðàíî 8 ðàáîò, èç êîòîðûõ 7 (n= 930) áûëè ïîñâÿùåíû ñíèæåíèþ ýôôåêòèâíîñòè äåéñòâèÿ ñòàòèíîâè3—ðàçâèòèþ ñòàòèí-èíäóöèðîâàííûõ ìèîïàòèé (â èññëåäîâàíèå âîøëî 58 ïàöèåíòîâ ñ ìèîïàòèåé è 239 áåç ìèîïàòèè).

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Su J, Xu H, Yang J, Yu Q, Yang S, Zhang J, et al.ABCB1C3435T polymorphism and the lipid-lowering response in hypercholesterolemic patients on statins: a meta-analysis. Lipids Health Dis. 2015; 14: 122.
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    Ñòàòèíû Âëèÿíèå ïîëèìîðôèçìà Ñ3435Ò ãåíàABCB1 íà ýôôåêòèâíîñòü è áåçîïàñíîñòü ïðèìåíåíèÿ ñòàòèíîâ ÿâëÿëîñü îáëàñòüþ èíòåðåñîâ ìíîãèõ èññëåäîâàòåëåé [21]. Â 2015 ã. êîëëåêòèâîì àâòîðîâ áûëè îïóáëèêîâàíû ðåçóëüòàòû ìåòà-àíàëèçà, îáîáùàþùèå îïûò ìíîãîëåòíèõ èññëåäîâàíèé ïîëèìîðôèçìà ãåíàABCB1
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    . Ñðåäè 140 èññëåäîâàíèé áûëî îòîáðàíî 8 ðàáîò, èç êîòîðûõ 7 (n= 930) áûëè ïîñâÿùåíû ñíèæåíèþ ýôôåêòèâíîñòè äåéñòâèÿ ñòàòèíîâè3—ðàçâèòèþ ñòàòèí-èíäóöèðîâàííûõ ìèîïàòèé (â èññëåäîâàíèå âîøëî 58 ïàöèåíòîâ ñ ìèîïàòèåé è 239 áåç ìèîïàòèè).

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McBride BF, Yang T, Roden DM. Influence of the G2677T/C3435T haplotype ofMDR1on P-glycoprotein trafficking and ibutilide-induced block of HERG. Pharmacogenomics J. 2009; 9(3): 194–201.
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    Íàïðèìåð, áûëî ïîêàçàíî, ÷òî ïðè ýêñïðåññèè Ð-ãëèêîïðîòåèíà â ÿéöåêëåòêàõ êèòàéñêîãî õîìÿ÷êà îäíîíóêëåîòèäíàÿ çàìåíà Ñ3435Ò ïðèâîäèò ê òîìó, ÷òî ãëèêîïðîòåèí, ïî íåÿñíûì ïðè÷èíàì, íå âûõîäèò íà ïîâåðõíîñòü êëåòêè è, ñîîòâåòñòâåííî, íå ôóíêöèîíèðóåò
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    . Íåîáõîäèìî òàêæå îòìåòèòü, ÷òî ìåòà-àíàëèç, ïðåäïîëàãàåìûé ýòàëîííûé èíñòðóìåíò ïðîâåðêè èñòèííîñòè íàëè÷èÿ àññîöèàöèè, â îïðåäåëåííûõ ñëó÷àÿõ òàêîâûì íå ÿâëÿåòñÿ. Íàïðèìåð, â ðàáîòó ìîãóò áûòü âêëþ÷åíû èññëåäîâàíèÿ, ïðîâåäåííûå â ðàçíûõ óñëîâèÿõ, ðàçëè÷àþùèåñÿ ìåòîäè÷åñêè è îñóùåñòâëåííûå íà ðàçíîðîäíîì ìàòåðèàëå (äîáðîâîëüöû/ïàöèåíòû, ðàçëè÷íàÿ ðàñîâàÿ èëè ýòíè÷åñêàÿ ïðèíàäëåæíîñòü, îäí

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Sokova EA. Monitoring post-approvial drug safety in pregnancy: pharmacogenetic aspects. Safety and Risk of Pharmacotherapy 2015; (3): 30–5 (in Russian). AUTHORS Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health
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    Ñðåäè ðàáîò, ïîñâÿùåííûõ ãåíåòèêå Ð-ãëèêîïðîòåèíà, áîëüøîé èíòåðåñ ïðåäñòàâëÿþò èññëåäîâàíèÿ, ñâÿçàííûå ñ îãðàíè÷åíèåì ïðîõîæäåíèÿ êñåíîáèîòèêîâ, âêëþ÷àÿ ËÑ, ÷åðåç ïëàöåíòó â ðàçâèâàþùèéñÿ ïëîä
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    . Òàêèå âîçäåéñòâèÿ ìîãóò ïðè÷èíÿòü ýìáðèîíó ñóùåñòâåííûé âðåä, ñòàíîâÿñü ïðè÷èíîé ñåðüåçíûõ îòêëîíåíèé ðàçâèòèÿ. Îäíàêî ýòà îáëàñòü èññëåäîâàíà åùå íåäîñòàòî÷íî, è íàáëþäåíèÿ, ñîãëàñíî êîòîðûì ïîëèìîðôèçìû ãåíàABCB1(â òîì ÷èñëå Ñ3435Ò) ìîãóò âûñòóïàòü ïðåäèêòîðîì îïðåäåëåííûõ ñîñòîÿíèé, íóæäàþòñÿ â ñåðüåçíîé íåçàâèñèìîé ïðîâåðêå.