The 19 references with contexts in paper E. Egorenkov A., V. Smirnov V., V. Kuzina N., S. Dementiev P., G. Ramenskaya V., Е. Егоренков А., В. Смирнов В., В. Кузина Н., С. Дементьев П., Г. Раменская В. (2018) “Методики фенотипирования изофермента CYP3A4, применяемые для персонализации фармакотерапии // CYP3A4 isoenzyme phenotyping for personalisation of pharmacotherapy” / spz:neicon:vedomostincesmp:y:2017:i:1:p:20-24

1
Denisov IG, Makris TM, Sligar SG, Schlichting I. Structure and chemistry of cytochrome P450. Chemical Reviews 2005; 105(6):
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    Ôåíîòèïè÷åñêèé ìåòîä, â ñâîþ î÷åðåäü, ïîëíîñòüþ ó÷èòûâàåò âîçäåéñòâèÿ îêðóæàþùåé ñðåäû íà îðãàíèçì, è â ðåçóëüòàòå âîçìîæíî ïîëó÷èòü äàííûå î ðåàëüíîé àêòèâíîñòè ìåòàáîëèçìà â äàííûé ìîìåíò âðåìåíè. Ìåòîä çàêëþ÷àåòñÿ â ïðÿìîì îïðåäåëåíèè àêòèâíîñòè òîãî èëè èíîãî ôåðìåíòà ìåòàáîëèçìà ËÑ ïî ôàðìàêîêèíåòèêå åãî ñïåöèôè÷åñêîãî ñóáñòðàòà («ìàðêåðíîãî »ñóáñòðàòà) è åãî ìåòàáîëèòà
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    . Ñóùåñòâóåò ìíîæåñòâî ìåòîäèê îïðåäåëåíèÿ àêòèâíîñòè ðàçëè÷íûõ èçîôåðìåíòîâ CYPin vivo, ñ èñïîëüçîâàíèåì ðàçëè÷íûõ âåùåñòâ â êà÷åñòâå ñóáñòðàòîâ-ìàðêåðîâ. Îäíèì èç ñàìûõ ñîâðåìåííûõ è ïåðñïåêòèâíûõ àíàëèòè÷åñêèõ ìåòîäîâ, èñïîëüçóåìûõ äëÿ êîëè÷åñòâåííîãî îïðåäåëåíèÿ êîíöåíòðàöèè ñóáñòðàòîâ-ìàðêåðîâ è èõ ìåòàáîëèòîâ â áèîæèäêîñòÿõ îðãàíèçìà ïðè ôåíîòèïèðîâàíèè, ÿâëÿåòñÿ ìåòîä âûñîêîýôôåêòèâíîé æ

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    Èçîôåðìåíòû öèòîõðîìà Ð450 ïî êëàññèôèêàöèè Nebert (1987) ïðèíÿòî ðàçäåëÿòü ïî áëèçîñòè (ãîìîëîãèè) íóêëåîòèä/àìèíîêèñëîòíîé ïîñëåäîâàòåëüíîñòè íà ñåìåéñòâà, à ïîñëåäíèå, â ñâîþ î÷åðåäü, íà ïîäñåìåéñòâà. Èçîôåðìåíòû öèòîõðîìà Ð450 ñ èäåíòè÷íîñòüþ àìèíîêèñëîòíîãî ñîñòàâà áîëåå 40 % îáúåäèíåíû â ñåìåéñòâà, êîòîðûõ âûäåëåíî 36; 12 èç íèõ îáíàðóæåíû ó ìëåêîïèòàþùèõ
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    . Ó êàæäîãî èç èçîôåðìåíòîâ CYP ñâîÿ ñïåöèôè÷åñêàÿ ôóíêöèÿ â ìåòàáîëè÷åñêèõ ïðîöåññàõ è ñâîé ñïåöèôè÷åñêèé ñóáñòðàò. Íåñìîòðÿ íà âñå èçîáèëèå èçîôåðìåíòîâ, ëèøü íåñêîëüêî èç íèõ äåëàþò îñíîâíîé âêëàä â ìåòàáîëèçì êñåíîáèîòèêîâ.

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    Îäíèì èç òàêèõ èçîôåðìåíòîâ ÿâëÿåòñÿ èçîôåðìåíò CYP3A4, îòâå÷àþùèé çà ìåòàáîëèçì ìíîãèõ âåùåñòâ êàê ýíäîãåííîãî ïðîèñõîæäåíèÿ (ñòåðîèäíûå ãîðìîíû, ëèïèäû, æåë÷íûå êèñëîòû), òàê è êñåíîáèîòèêîâ, âêëþ÷àÿ ëåêàðñòâåííûå âåùåñòâà, òîêñè÷íûå âåùåñòâà îêðóæàþùåé ñðåäû è ïðèðîäíûå ñîåäèíåíèÿ, ñîäåðæàùèåñÿ â ïðîäóêòàõ ïèòàíèÿ
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    . Äàííûé èçîôåðìåíò ñ÷èòàåòñÿ îñíîâíûì èç âñåõ èçîôåðìåíòîâ CYP, ïîñêîëüêó åãî äîëÿ â îðãàíèçìå ñîñòàâëÿåò îêîëî 80 % îò âñåãî êîëè÷åñòâà èçîôåðìåíòîâ CYP, ïðè ýòîì îí îáíàðóæèâàåòñÿ íå òîëüêî â ïå÷åíè, íî è â ïðîñòàòå, ìîëî÷íûõ æåëåçàõ, êëåòêàõ ýïèòåëèÿ òîíêîãî è òîëñòîãî êèøå÷íèêà, è äàæå â êëåòêàõ ãîëîâíîãî ìîçãà [3, 4].

2
53–77. 2. Domanski TL, He YA, Khan KK, Roussel F, Wang Q, Halpert JR. Phenylalanine and tryptophan scanning mutagenesis of CYP3A4 substrate recognition site residues and effect on substrate oxidation and cooperativity. Biochemistry 2001; 40(34): 10150–60.
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    Îäíèì èç òàêèõ èçîôåðìåíòîâ ÿâëÿåòñÿ èçîôåðìåíò CYP3A4, îòâå÷àþùèé çà ìåòàáîëèçì ìíîãèõ âåùåñòâ êàê ýíäîãåííîãî ïðîèñõîæäåíèÿ (ñòåðîèäíûå ãîðìîíû, ëèïèäû, æåë÷íûå êèñëîòû), òàê è êñåíîáèîòèêîâ, âêëþ÷àÿ ëåêàðñòâåííûå âåùåñòâà, òîêñè÷íûå âåùåñòâà îêðóæàþùåé ñðåäû è ïðèðîäíûå ñîåäèíåíèÿ, ñîäåðæàùèåñÿ â ïðîäóêòàõ ïèòàíèÿ
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    . Äàííûé èçîôåðìåíò ñ÷èòàåòñÿ îñíîâíûì èç âñåõ èçîôåðìåíòîâ CYP, ïîñêîëüêó åãî äîëÿ â îðãàíèçìå ñîñòàâëÿåò îêîëî 80 % îò âñåãî êîëè÷åñòâà èçîôåðìåíòîâ CYP, ïðè ýòîì îí îáíàðóæèâàåòñÿ íå òîëüêî â ïå÷åíè, íî è â ïðîñòàòå, ìîëî÷íûõ æåëåçàõ, êëåòêàõ ýïèòåëèÿ òîíêîãî è òîëñòîãî êèøå÷íèêà, è äàæå â êëåòêàõ ãîëîâíîãî ìîçãà [3, 4].

3
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology and Therapeutics 2013; 138(1): 103–41.
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    Äàííûé èçîôåðìåíò ñ÷èòàåòñÿ îñíîâíûì èç âñåõ èçîôåðìåíòîâ CYP, ïîñêîëüêó åãî äîëÿ â îðãàíèçìå ñîñòàâëÿåò îêîëî 80 % îò âñåãî êîëè÷åñòâà èçîôåðìåíòîâ CYP, ïðè ýòîì îí îáíàðóæèâàåòñÿ íå òîëüêî â ïå÷åíè, íî è â ïðîñòàòå, ìîëî÷íûõ æåëåçàõ, êëåòêàõ ýïèòåëèÿ òîíêîãî è òîëñòîãî êèøå÷íèêà, è äàæå â êëåòêàõ ãîëîâíîãî ìîçãà
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    . CYP3A4 ìåòàáîëèçèðóåò áîëåå ïîëîâèíû èñïîëüçóåìûõ íà ñåãîäíÿøíèé äåíü ëåêàðñòâåííûõ ïðåïàðàòîâ, âêëþ÷àÿ ïðîòèâîîïóõîëåâûå, èììóíîäåïðåññàíòû, ïðîòèâîãðèáêîâûå, ìàêðîëèäû, òðèöèêëè÷åñêèå àíòèäåïðåññàíòû è ìíîãèå äðóãèå.

4
Ferguson CS, Tyndale RF. Cytochrome P450 enzymes in the brain: emerging evidence of biological significance. Trends in Pharmacological Sciences 2011; 32(12): 708–14.
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    Äàííûé èçîôåðìåíò ñ÷èòàåòñÿ îñíîâíûì èç âñåõ èçîôåðìåíòîâ CYP, ïîñêîëüêó åãî äîëÿ â îðãàíèçìå ñîñòàâëÿåò îêîëî 80 % îò âñåãî êîëè÷åñòâà èçîôåðìåíòîâ CYP, ïðè ýòîì îí îáíàðóæèâàåòñÿ íå òîëüêî â ïå÷åíè, íî è â ïðîñòàòå, ìîëî÷íûõ æåëåçàõ, êëåòêàõ ýïèòåëèÿ òîíêîãî è òîëñòîãî êèøå÷íèêà, è äàæå â êëåòêàõ ãîëîâíîãî ìîçãà
    Exact
    [3, 4]
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    . CYP3A4 ìåòàáîëèçèðóåò áîëåå ïîëîâèíû èñïîëüçóåìûõ íà ñåãîäíÿøíèé äåíü ëåêàðñòâåííûõ ïðåïàðàòîâ, âêëþ÷àÿ ïðîòèâîîïóõîëåâûå, èììóíîäåïðåññàíòû, ïðîòèâîãðèáêîâûå, ìàêðîëèäû, òðèöèêëè÷åñêèå àíòèäåïðåññàíòû è ìíîãèå äðóãèå.

6
Ratajewski M, Walczak-Drzewiecka A,Sa³kowskaA, Dastych J. Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor. Toxicological Letters 2011; 205(2): 146–53.
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    Òàê êàê äàííûé èçîôåðìåíò ñîäåðæèò áîëüøîå êîëè÷åñòâî ñóáñòðàòîâ, ðàâíî êàê èíãèáèòîðîâ è èíäóêòîðîâ, çà÷àñòóþ ïðîèñõîäèò èçìåíåíèå àêòèâíîñòè CYP3A4, âûçâàííîå êàê âçàèìîäåéñòâèåì ËÑ, òàê è âîçäåéñòâèåì êñåíîáèîòèêîâ èç îêðóæàþùåé ñðåäû è ïðîäóêòîâ ïèòàíèÿ (íàïðèìåð, ïðèðîäíûå ñîåäèíåíèÿ ãðåéïôðóòîâîãî ñîêà ïîäàâëÿþò àêòèâíîñòü CYP3A4)
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    [6–8]
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    . ÌÅÒÎÄÈÊÈ ÎÏÐÅÄÅËÅÍÈß ÀÊÒÈÂÍÎÑÒÈ CYP3A4 Ïåðâûì èç øèðîêî ïðèìåíÿåìûõ â êëèíè÷åñêîé ïðàêòèêå ìåòîäîâ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4 ÿâëÿåòñÿ ýðèòðîìèöèí-äûõàòåëüíûé òåñò (erythromycin breath test, ERMBT).

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Elens L, Nieuweboer AJ, Clarke SJ, Charles KA, de Graan AJ, Haufroid V, van Gelder T, Mathijssen RH, van Schaik RH. Impact of POR*28 on the clinical pharmacokinetics of CYP3A phenotyping probes midazolam and erythromycin. Pharmacogenet Genomics 2013; 23(3): 148–55.
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    Ïàöèåíòàì âíóòðèâåííî ââîäèòñÿ äîçà ìå÷åíîãî ýðèòðîìèöèíà, ñîîòâåòñòâóþùàÿ 4 ìèêðîêþðè (îêîëî 100 ìã), è ÷åðåç 20 ìèí èñïûòóåìûì ïðåäëàãàåòñÿ íàäóòü âîçäóøíûé øàðèê, ïîñëå ÷åãî ïðîâîäèòñÿ êîëè÷åñòâåííîå îïðåäåëåíèå14CO2â îáúåìå âûäåëåííîãî âîçäóõà ðàäèîìåòðè÷åñêèì ìåòîäîì
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    . Ïî ïîëó÷åííûì äàííûì ðàññ÷èòûâàåòñÿ ìåòàáîëè÷åñêîå îòíîøåíèå êîëè÷åñòâà âûäåëåííîãî ìåòàáîëèòà ê êîëè÷åñòâó ââåäåííîãî ñóáñòðàòà, ïî çíà÷åíèþ êîòîðîãî îöåíèâàåòñÿ àêòèâíîñòü CYP3A4. Íåäîñòàòêàìè äàííîãî ìåòîäà ÿâëÿþòñÿ íåîáõîäèìîñòü èñïîëüçîâàíèÿ âåùåñòâà ñ èçîòîïíîé ìåòêîé, èíâàçèâíîñòü ìåòîäà è íåîáõîäèìîñòü ïðîâåäåíèÿ àíàëèçà â ñòàöèîíàðå ââèäó âíóòðèâåííîãî ââåäåíèÿ ñóáñòðàòà-ìàðêåðà, ñð

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KivistöKT, Kroemer HK. Use of Probe Drugs as Predictors of Drug Metabolism in Humans. The Journal of Clinical Pharmacology 1997; 37(1 Suppl): 40–8.
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    ìåòêîé, èíâàçèâíîñòü ìåòîäà è íåîáõîäèìîñòü ïðîâåäåíèÿ àíàëèçà â ñòàöèîíàðå ââèäó âíóòðèâåííîãî ââåäåíèÿ ñóáñòðàòà-ìàðêåðà, ñðàâíèòåëüíàÿ ñëîæíîñòü ïðîâåäåíèÿ ðàäèîìåòðè÷åñêîãî àíàëèçà ââèäó ìàëîé ðàñïðîñòðàíåííîñòè äàííîãî ìåòîäà â ëàáîðàòîðíîé ïðàêòèêå, à òàêæå íåäîñòàòî÷íàÿ òî÷íîñòü îïðåäåëåíèÿ àêòèâíîñòè ïî ñðàâíåíèþ ñ ðàçðàáîòàííûìè â ïîñëåäóþùåì ìåòîäèêàìè ôåíîòèïèðîâàíèÿ CYP3A4
    Exact
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    . Äëÿ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4 òàêæå ðàçðàáîòàíû ìåòîäèêè ñ èñïîëüçîâàíèåì ðàçëè÷íûõ ëåêàðñòâåííûõ âåùåñòâ â êà÷åñòâå ñóáñòðàòîâ-ìàðêåðîâ. Òàêèìè ñóáñòðàòàìè ÿâëÿþòñÿ õèíèí è ìèäàçîëàì. Ðàçðàáîòàíî ìíîæåñòâî ìåòîäèê, èñïîëüçóþùèõ äàííûå âåùåñòâà â êà÷åñòâå ñóáñòðàòîâ, íî íåñìîòðÿ íà èõ ðàçëè÷èÿ ìåæäó ñîáîé, îñíîâíîé ïðèíöèï ïðîâåäåíèÿ èññëåäîâàíèÿ îñòàåòñÿ îäíèì è òåì æå.

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Rivory LP, Slaviero K, Seale JP, Hoskins JM, Boyer M, Beale PJ, et al. Optimizing the erythromycin breath test for use in cancer patients. Clinical Cancer Research 2000; 6(9): 3480–5.
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    ìåòêîé, èíâàçèâíîñòü ìåòîäà è íåîáõîäèìîñòü ïðîâåäåíèÿ àíàëèçà â ñòàöèîíàðå ââèäó âíóòðèâåííîãî ââåäåíèÿ ñóáñòðàòà-ìàðêåðà, ñðàâíèòåëüíàÿ ñëîæíîñòü ïðîâåäåíèÿ ðàäèîìåòðè÷åñêîãî àíàëèçà ââèäó ìàëîé ðàñïðîñòðàíåííîñòè äàííîãî ìåòîäà â ëàáîðàòîðíîé ïðàêòèêå, à òàêæå íåäîñòàòî÷íàÿ òî÷íîñòü îïðåäåëåíèÿ àêòèâíîñòè ïî ñðàâíåíèþ ñ ðàçðàáîòàííûìè â ïîñëåäóþùåì ìåòîäèêàìè ôåíîòèïèðîâàíèÿ CYP3A4
    Exact
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    . Äëÿ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4 òàêæå ðàçðàáîòàíû ìåòîäèêè ñ èñïîëüçîâàíèåì ðàçëè÷íûõ ëåêàðñòâåííûõ âåùåñòâ â êà÷åñòâå ñóáñòðàòîâ-ìàðêåðîâ. Òàêèìè ñóáñòðàòàìè ÿâëÿþòñÿ õèíèí è ìèäàçîëàì. Ðàçðàáîòàíî ìíîæåñòâî ìåòîäèê, èñïîëüçóþùèõ äàííûå âåùåñòâà â êà÷åñòâå ñóáñòðàòîâ, íî íåñìîòðÿ íà èõ ðàçëè÷èÿ ìåæäó ñîáîé, îñíîâíîé ïðèíöèï ïðîâåäåíèÿ èññëåäîâàíèÿ îñòàåòñÿ îäíèì è òåì æå.

12
Christensen M, Andersson K, Dalen P, Mirghani RA, Muirhead GJ, Nordmark A, et al. The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes. Journal of Clinical Pharmacy and Therapeutics 2003; 73: 517–28.
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    Áèîîáúåêò ìîæåò îòáèðàòüñÿ êàê îäíîêðàòíî, òàê è ìíîãîêðàòíî â òå÷åíèå 48–96 ÷ äëÿ îöåíêè èçìåíåíèÿ çíà÷åíèÿ ìåòàáîëè÷åñêîãî îòíîøåíèÿ âî âðåìåíè. Íèæå ïðèâåäåíû îáîáùåííûå ñõåìû ïðîâåäåíèÿ èññëåäîâàíèé ïî îöåíêå àêòèâíîñòè CYP3A4 ñ èñïîëüçîâàíèåì ìèäàçîëàìà è õèíèíà
    Exact
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    . Õèíèí ïðåäñòàâëÿåò ñîáîé àëêàëîèä, ñîäåðæàùèéñÿ â êîðå õèííîãî äåðåâà, îáëàäàþùèé ÿðêî âûðàæåííûì ïðîòèâîìàëÿðèéíûì äåéñòâèåì. Ïîñëå ïîïàäàíèÿ â îðãàíèçì õèíèí ìåòàáîëèçèðóåòñÿ CYP3A4 ñ îáðàçîâàíèåì ñïåöèôè÷åñêîãî ìåòàáîëèòà 3-ãèäðîêñèõèíèíà [17].

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Yin QQ, Lam SS, Lo CM, Chow MS. Rapid determination of five probe drugs and their metabolites in human plasma and urine by liquid chromatography/tandem mass spectrometry: application to cytochrome P450 phenotyping studies. Rapid Communications in Mass Spectrometry 2004; 18: 2921–33.
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    ÌÅÒÎÄÈÊÈ ÎÏÐÅÄÅËÅÍÈß ÀÊÒÈÂÍÎÑÒÈ CYP3A4 Ïåðâûì èç øèðîêî ïðèìåíÿåìûõ â êëèíè÷åñêîé ïðàêòèêå ìåòîäîâ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4 ÿâëÿåòñÿ ýðèòðîìèöèí-äûõàòåëüíûé òåñò (erythromycin breath test, ERMBT).  îñíîâå ìåòîäà ëåæèò êîëè÷åñòâåííîå îïðåäåëåíèå â âûäûõàåìîì âîçäóõå 14CO2, îáðàçóþùåãîñÿ â ðåçóëüòàòå áèîòðàíñôîðìàöèè ââåäåííîãî
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    [14C–N–ìåòèë]
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    -ýðèòðîìèöèíà. Ïàöèåíòàì âíóòðèâåííî ââîäèòñÿ äîçà ìå÷åíîãî ýðèòðîìèöèíà, ñîîòâåòñòâóþùàÿ 4 ìèêðîêþðè (îêîëî 100 ìã), è ÷åðåç 20 ìèí èñïûòóåìûì ïðåäëàãàåòñÿ íàäóòü âîçäóøíûé øàðèê, ïîñëå ÷åãî ïðîâîäèòñÿ êîëè÷åñòâåííîå îïðåäåëåíèå14CO2â îáúåìå âûäåëåííîãî âîçäóõà ðàäèîìåòðè÷åñêèì ìåòîäîì [9].

17
Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L. Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man. European Journal of Clinical Pharmacology 2003; 59(1): 23–8.
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    Õèíèí ïðåäñòàâëÿåò ñîáîé àëêàëîèä, ñîäåðæàùèéñÿ â êîðå õèííîãî äåðåâà, îáëàäàþùèé ÿðêî âûðàæåííûì ïðîòèâîìàëÿðèéíûì äåéñòâèåì. Ïîñëå ïîïàäàíèÿ â îðãàíèçì õèíèí ìåòàáîëèçèðóåòñÿ CYP3A4 ñ îáðàçîâàíèåì ñïåöèôè÷åñêîãî ìåòàáîëèòà 3-ãèäðîêñèõèíèíà
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    [17]
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    . Äëÿ ïðîâåäåíèÿ èññëåäîâàíèÿ ïàöèåíòó îäíîêðàòíî ââîäèòñÿ 500 ìã õèíèíà ãèäðîõëîðèäà, è ÷åðåç 4–6 ÷ ïîñëå ïðèåìà õèíèíà ïðîèçâîäèòñÿ âçÿòèå îáðàçöà êðîâè äëÿ îïðåäåëåíèÿ êîíöåíòðàöèé õèíèíà è åãî ìåòàáîëèòà â ïëàçìå êðîâè.

18
Lin YS, Lockwood GF, Graham MA, Brian WR, Loi CM, Dobrinska MR, et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration. Pharmacogenetics 2001; 11(9): 781–91.
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    Ìèäàçîëàì — ïðîèçâîäíîå áåíçîäèàçåïèíà, ñíîòâîðíûé ïðåïàðàò êîðîòêîãî äåéñòâèÿ, ïðèìåíÿþùèéñÿ äëÿ ëå÷åíèÿ îñòðûõ ýïèëåïòè÷åñêèõ ïðèïàäêîâ è óìåðåííî òÿæåëîé áåññîííèöû.  ïðîöåññå ðåàêöèè áèîòðàíñôîðìàöèè, êàòàëèçèðóåìîé èçîôåðìåíòîì CYP3A4, ìèäàçîëàì îêèñëÿåòñÿ äî 1¢-ãèäðîêñèìèäàçîëàìà
    Exact
    [18]
    Suffix
    . Ïàöèåíòó îäíîêðàòíî ââîäèòñÿ 2 ìã ìèäàçîëàìà, è ÷åðåç 4 ÷ ïîñëå ââåäåíèÿ îòáèðàåòñÿ êðîâü äëÿ ïðîâåäåíèÿ êîëè÷åñòâåííîãî îïðåäåëåíèÿ ìèäàçîëàìà è åãî ìåòàáîëèòà â ïëàçìå êðîâè. Êîëè÷åñòâåííîå îïðåäåëåíèå òàêæå ïðîâîäèòñÿ ìåòîäîì âûñîêîýôôåêòèâíîé æèäêîñòíîé õðîìàòîãðàôèè.

19
El Desoky ES, Mohamed HO, Farghaly WM, Hamed SA, Hedaya MA, Siest JP. Study of urinary 6 beta-hydroxycortisol/cortisol ratio in spot urine sample as a biomarker of 3A4 enzyme activity in healthy and epileptic subjects of Egyptian population. Pharmacological Research 2005; 51(6): 575–80.
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    Êîëè÷åñòâåííîå îïðåäåëåíèå òàêæå ïðîâîäèòñÿ ìåòîäîì âûñîêîýôôåêòèâíîé æèäêîñòíîé õðîìàòîãðàôèè. Ïðèâåäåííûå âûøå ìåòîäèêè îïðåäåëåíèÿ àêòèâíîñòè CYP3A4 èìåþò ðÿä íåäîñòàòêîâ. Ê òàêîâûì ìîæíî îòíåñòè èñïîëüçîâàíèå âåùåñòâ ñ ðàäèîàêòèâíîé ìåòêîé
    Exact
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    , à òàêæå èñïîëüçîâàíèå ôàðìàêîëîãè÷åñêè àêòèâíûõ âåùåñòâ. Ê òîìó æå, ïðè âíóòðèâåííîì ââåäåíèè ñóáñòðàòîâ-ìàðêåðîâ îöåíèâàåòñÿ àêòèâíîñòü ôåðìåíòà CYP3A4, íàõîäÿùåãîñÿ â ãåïàòîöèòàõ, íî íå îöåíèâàåòñÿ àêòèâíîñòü CYP3A4 â òîíêîì êèøå÷íèêå.

20
Shibasaki H, Hosoda K, Goto M, Suzuki A, Yokokawa A, Ishii K, et al. Intraindividual and interindividual variabilities in endogenous cortisol 6b-hydroxylation clearance as an index forin vivoCYP3A phenotyping in humans. Drug Metab Dispos. 2013; 41(2): 475–9.
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  1. In-text reference with the coordinate start=9989
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    Ê òîìó æå, ïðè âíóòðèâåííîì ââåäåíèè ñóáñòðàòîâ-ìàðêåðîâ îöåíèâàåòñÿ àêòèâíîñòü ôåðìåíòà CYP3A4, íàõîäÿùåãîñÿ â ãåïàòîöèòàõ, íî íå îöåíèâàåòñÿ àêòèâíîñòü CYP3A4 â òîíêîì êèøå÷íèêå. Íàêîíåö, äàííûå ìåòîäû ñðàâíèòåëüíî äîðîãè è äëèòåëüíû
    Exact
    [20]
    Suffix
    .  äàëüíåéøåì áûëè ðàçðàáîòàíû ìåòîäèêè, èñïîëüçóþùèå â êà÷åñòâå ñóáñòðàòà-ìàðêåðîâ ýíäîãåííûå âåùåñòâà, ìåòàáîëèçèðóþùèåñÿ èçîôåðìåíòîì CYP3A4. Òàê, äàííûé èçîôåðìåíò ïðåèìóùåñòâåííî êàòàëèçèðóåò ðåàêöèþ ãèäðîêñèëèðîâàíèÿ êîðòèçîëà, â ðåçóëüòàòå ÷åãî îáðàçóåòñÿ 6b-ãèäðîêñèêîðòèçîë [21].

21
Shibasaki H, Kuroiwa M, Uchikura S, Tsuboyama S, Yokokawa A, Kume M, et al. Use of endogenous cortisol 6b-hydroxylation clearance for phenotypingin vivoCYP3A activity in women after sequential administration of an oral contraceptive (OC) containing ethinylestradiol and levonorgestrel as weak CYP3A inhibitors. Steroids 2014; 87: 137–44.
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     äàëüíåéøåì áûëè ðàçðàáîòàíû ìåòîäèêè, èñïîëüçóþùèå â êà÷åñòâå ñóáñòðàòà-ìàðêåðîâ ýíäîãåííûå âåùåñòâà, ìåòàáîëèçèðóþùèåñÿ èçîôåðìåíòîì CYP3A4. Òàê, äàííûé èçîôåðìåíò ïðåèìóùåñòâåííî êàòàëèçèðóåò ðåàêöèþ ãèäðîêñèëèðîâàíèÿ êîðòèçîëà, â ðåçóëüòàòå ÷åãî îáðàçóåòñÿ 6b-ãèäðîêñèêîðòèçîë
    Exact
    [21]
    Suffix
    . Äàííûé ìåòàáîëèò âûäåëÿåòñÿ ñ ìî÷îé è ìîæåò áûòü èñïîëüçîâàí êàê ñïåöèôè÷åñêèé ìàðêåð äëÿ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4. Òàêæå â êà÷åñòâå ïàðû ñóáñòðàò/ìåòàáîëèò ìîãóò áûòü èñïîëüçîâàíû õîëåñòåðèí/4b-ãèäðîêñèõîëåñòåðèí [22, 23].

22
Graan AJ, Sparreboom A, de Bruijn P, de Jonge E, van der Holt B, Wiemer EAC, et al. 4b-hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes. British Journal of clinical pharmacology 2015; 80(3): 560–8.
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    Äàííûé ìåòàáîëèò âûäåëÿåòñÿ ñ ìî÷îé è ìîæåò áûòü èñïîëüçîâàí êàê ñïåöèôè÷åñêèé ìàðêåð äëÿ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4. Òàêæå â êà÷åñòâå ïàðû ñóáñòðàò/ìåòàáîëèò ìîãóò áûòü èñïîëüçîâàíû õîëåñòåðèí/4b-ãèäðîêñèõîëåñòåðèí
    Exact
    [22, 23]
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    .  êà÷åñòâå áèîîáúåêòà èñïîëüçóåòñÿ ìî÷à, ñîáðàííàÿ â ïåðèîäñ8äî 12 ÷àñîâ óòðà. Êîëè÷åñòâåííîå îïðåäåëåíèå ñóáñòðàòà è ìåòàáîëèòà ìîæåò áûòü ïðîâåäåíî êàê èììóíîõèìè÷åñêèì ìåòîäîì àíàëèçà, òàê è ìåòîäîì âûñîêîýôôåêòèâíîé æèäêîñòíîé õðîìàòîãðàôèè [24].

23
Tomalik-Scharte D, Lütjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U. Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clinical Pharmacology and Therapeutics 2009; 86(2): 147–53.
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    Äàííûé ìåòàáîëèò âûäåëÿåòñÿ ñ ìî÷îé è ìîæåò áûòü èñïîëüçîâàí êàê ñïåöèôè÷åñêèé ìàðêåð äëÿ îïðåäåëåíèÿ àêòèâíîñòè CYP3A4. Òàêæå â êà÷åñòâå ïàðû ñóáñòðàò/ìåòàáîëèò ìîãóò áûòü èñïîëüçîâàíû õîëåñòåðèí/4b-ãèäðîêñèõîëåñòåðèí
    Exact
    [22, 23]
    Suffix
    .  êà÷åñòâå áèîîáúåêòà èñïîëüçóåòñÿ ìî÷à, ñîáðàííàÿ â ïåðèîäñ8äî 12 ÷àñîâ óòðà. Êîëè÷åñòâåííîå îïðåäåëåíèå ñóáñòðàòà è ìåòàáîëèòà ìîæåò áûòü ïðîâåäåíî êàê èììóíîõèìè÷åñêèì ìåòîäîì àíàëèçà, òàê è ìåòîäîì âûñîêîýôôåêòèâíîé æèäêîñòíîé õðîìàòîãðàôèè [24].

24
Smirnov VV. Development of methods for determining cortisol and 6-b-hydroxycortisol in the urine in order to determine the activity of CYP3A4. Cand. Pharm. Sci [dissertation]. Moscow; 2011 (in Russian).
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     êà÷åñòâå áèîîáúåêòà èñïîëüçóåòñÿ ìî÷à, ñîáðàííàÿ â ïåðèîäñ8äî 12 ÷àñîâ óòðà. Êîëè÷åñòâåííîå îïðåäåëåíèå ñóáñòðàòà è ìåòàáîëèòà ìîæåò áûòü ïðîâåäåíî êàê èììóíîõèìè÷åñêèì ìåòîäîì àíàëèçà, òàê è ìåòîäîì âûñîêîýôôåêòèâíîé æèäêîñòíîé õðîìàòîãðàôèè
    Exact
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    . Ìåòîäû, èñïîëüçóþùèå ýíäîãåííûå âåùåñòâà â êà÷åñòâå ñïåöèôè÷åñêèõ ìàðêåðîâ, îáëàäàþò ðÿäîì ïðåèìóùåñòâ. Îíè ïîçâîëÿþò îïðåäåëèòü àêòèâíîñòü ôåðìåíòà âî âñåì îðãàíèçìå, à íå òîëüêî ëèøü â ïå÷åíè; äàííûå ìåòîäû ïîçâîëÿþò îïðåäåëèòü èñêîìûå âåùåñòâà â ìî÷å, ÷òî ñíèæàåò èíâàçèâíîñòü ìåòîäà è îáëåã÷àåò ïðîöåäóðó ñáîðà áèîìàòåðèàëà; â ïðîöåññå îïðåäåëåíèÿ àêòèâíîñòè èçîôåðìåíòà íå èñïîëüçóþòñÿ êàêèå-ë

25
Smirnov VV, Savchenko AYu, Ramenskaya GV. Development and validation of methods of quantitative determination of endogenous cortisol and 6-b-hydroxycortisol in the urine in order to determine the activity of the isoenzyme CYP3A4. Biomeditsina 2010; 1(4): 56–60 (in Russian).
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    àêòèâíîñòü ôåðìåíòà âî âñåì îðãàíèçìå, à íå òîëüêî ëèøü â ïå÷åíè; äàííûå ìåòîäû ïîçâîëÿþò îïðåäåëèòü èñêîìûå âåùåñòâà â ìî÷å, ÷òî ñíèæàåò èíâàçèâíîñòü ìåòîäà è îáëåã÷àåò ïðîöåäóðó ñáîðà áèîìàòåðèàëà; â ïðîöåññå îïðåäåëåíèÿ àêòèâíîñòè èçîôåðìåíòà íå èñïîëüçóþòñÿ êàêèå-ëèáî ýêçîãåííûå âåùåñòâà, ÷òî ñâîäèò ê ìèíèìóìó ðèñê âîçíèêíîâåíèÿ ðàçëè÷íûõ íåæåëàòåëüíûõ ðåàêöèé ËÑ â ïðîöåññå èññëåäîâàíèÿ
    Exact
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    . ÇÀÊËÞ×ÅÍÈÅ Íåñìîòðÿ íà òî, ÷òî ñóùåñòâóþò ðàçëè÷íûå ìåòîäèêè îïðåäåëåíèÿ àêòèâíîñòè èçîôåðìåíòà CYP3A4, ìíîãèå èç íèõ îáëàäàþò ðÿäîì íåäîñòàòêîâ. Äëÿ óìåíüøåíèÿ ðèñêà âîçíèêíîâåíèÿ íåæåëàòåëüíûõ ðåàêöèé ËÑ è èíâàçèâíîñòè ìåòîäà ñëåäóåò îòêàçàòüñÿ îò èñïîëüçîâàíèÿ ýêçîãåííûõ ñóáñòðàòîâ.