DETERMINATION OF 3-HYDROXY-3-PYRROLINE-2-ONE IN URINE AND STUDY OF ITS EXCRETION FROM THE ORGANISM OF LABORATORY ANIMALS


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Abstract

It is known that almost any disease of the central nervous system is accompanied by the development of cognitive disorders. The drugs of choice in the complex therapy in this case are nootropics. On the world market racetam group, i.e. derivatives of alpha-pyrrolidone, prevails among nootropics, and the derivatives have a wide spectrum of pharmacological activity. Currently, this group continues to expand. By the employees of Perm State Pharmaceutical Academy (PSPA), ruled by Professor V.L. Gein, a new biologically active compound, a 3-pyrrolin-2-one derivative KOH-1 was synthesized. This compound is at the preclinical research stage now.The aim of this work was the development of methods for determination of KOH-1 in urine by high performance liquid chromatography (HPLC), the study of excretion KOH-1 from the organism of laboratory animals.Materials and methods. Studies on the development of methods were carried out by using a liquid chromatograph LC-20 Prominence (Shimadzu, Japan) with a diode-array detector. The validation was carried out in accordance with the requirements for bioanalytical methods, in terms of selectivity, linearity, precision and accuracy. The study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g. The substance KOH-1 was administered once orally in a suspension of starch mucus at a dose of 100 mg/kg.Results and discussion. As a result of the research, the  method for determining the biologically active compound KOH-1 in urine has been developed. The validation showed its suitability for pharmacokinetic studies. The data on daily excretion of KOH-1 in urine after a single oral administration to rats were obtained.Conclusion. The developed conditions for the chromatographic determination of KOH-1 in urine can be used in pharmacokinetic studies, both at the preclinical and clinical stages of the study of a potential drug. The data on excretion of KOH-1 will allow to determine the ways of excretion of the preparation, and also to select a rational dosage, to identify possible contraindications to the use.

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Pharmacy & Pharmacology V. 5 N 4, 2017ɍȾКОʿˀʫʪʫЛʫʻʰʫʿˀОʰʯʦОʪʻОʧОͳʧʰʪˀОКˁʰͳͳʿʰˀˀОЛʰʻͳͳОʻʤʰʯ˄ЧʫʻʰʫʫʧОˑКˁКˀʫˉʰʰОˀʧʤʻʰʯʺʤЛʤʥОˀʤ˃ОˀʻˏˈʮʰʦО˃ʻˏˈȻɭлɝɚкоɜɚКɚɪпɟнкоɎȽȻОɍПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияМинзɞɪɚɜɚɊоɫɫииɊоɫɫияПɟɪмьПолɟɜɚяИзɜɟɫɬнопɪɚкɬичɟɫкилюɛоɟзɚɛолɟɜɚниɟцɟнɬɪɚльнойɫиɫɬɟмыɫопɪоɜожɞɚɟɬɫяɪɚзɜиɬиɟмкоɝниɬиɜныɯПɪɟпɚɪɚɬɚмиɜыɛоɪɚɫоɫɬɚɜɟкомплɟкɫнойɞɚнномɫлɭчɚɟмиɪоɜомɪынкɟɫɪɟɞипɪɟоɛлɚɞɚɟɬɝɪɭппɚɪɚцɟɬɚпɪоизɜоɞныɯпиɪɪолиɞонɚɯɚɪɚкɬɟɪизɭющɚяɫяɫпɟкɬɪомɮɚɪмɚколоɝичɟɫкойɚкɬиɜнонɚɫɬоящɟɟɜɪɟмяɝɪɭппɚпɪоɞолжɚɟɬɪɚɫшиɪяɬьɫяɋоɬɪɭɞникɚмиПɟɪмɫкойɝоɫɭɞɚɪɫɬɜɟннойɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмиипоɞɪɭкоɜоɞɫɬɜомпɪоɮɟɫɫоɪɚȽɟйнɚɛылоɫинɬɟзиɪоɜɚноноɜоɟɛиолоɝичɟɚкɬиɜноɟɫоɟɞинɟниɟпɪоизɜоɞноɟ 3-ɝиɞɪокɫипиɪɪолин ? КОНкоɬоɪоɟɫɟйчɚɫпɪоɯоɞиɬэɬɚпɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийЦɟльюнɚɫɬоящɟйɪɚɛоɬыяɜилɚɫьɪɚзɪɚɛоɬкɚмɟɬоɞикиопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииȼЭЖɏɬɚкжɟизɭчɟниɟэкɫкɪɟцииКОНоɪɝɚнизмɚлɚɛоɪɚɬоɪныɯжиɜоɬныɯМɚɬɟɪиɚлымɟɬоɞыИɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟмɟɬоɞикипɪоɜоɞилииɫпользоɜɚниɟмжиɞкоɫɬноɝоɯɪомɚɬоɝɪɚɮɚ LC-20 Prominence (Shimadzu, ɞиоɞномɚɞɟɬɟкɬоɪомоɫɭщɟɫɬɜлялиɫооɬɜɟɬɫɬɜииɬɪɟɛоɜɚниямипɪɟɞъяɜляɟмымиɚнɚлиɬичɟɫкиммɟɬоɞикɚмпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьЭкɫкɪɟциюКОНизɭчɚлиɛɟлыɯнɟлинɟйныɯкɪыɫɚɯмɚɫɫой 300?400 поɫлɟоɞнокɪɚɬноɝоɜɜɟɞɟнияɞозɟ 100 ɊɟзɭльɬɚɬыоɛɫɭжɞɟниɟɪɟзɭльɬɚɬɟиɫɫлɟɞоɜɚнийɪɚзɪɚɛоɬɚнɚмɟɬоɞикɚопɪɟɞɟлɟнияɛиолоɝичɟɫкиɚкɬиɜноɝоɫоɟɞинɟнияКОНмочɟПɪоɜɟɞɟннɚяɜɚлиɞɚцияпокɚзɚлɚпɪиɝоɞɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнийПолɭчɟныɫɭɬочномɭɜыɜɟɞɟниюКОНмочойпоɫлɟоɞнокɪɚɬноɝоɜɜɟɞɟниякɪыɫɚмЗɚключɟниɟɊɚзɪɚɛоɬɚнныɟɭɫлоɜияɯɪомɚɬоɝɪɚɮичɟɫкоɝоопɪɟɞɟлɟнияКОНмочɟиɫпользоɜɚныɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯкɚкɞоклиничɟɫкомɬɚкклиничɟɫкомэɬɚпɚɯизɭчɟниялɟкɚɪɫɬɜɟнноɝоɫɪɟɞɫɬɜɚэкɫкɪɟцииКОНпозɜоляɬопɪɟɞɟлиɬьɜыɜɟɞɟнияпɪɟпɚɪɚɬɚɬɚкжɟпоɞоɛɪɚɬьɞозиɜозможныɟпɪоɬиɜопокɚзɚнияКлючɟɜыɟɫлоɜɚКОНɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоɝɪɚɮияɜɚлиɞɚциямɚкокинɟɬикɚциɬиɪоɜɚнияȻɭлɝɚкоɜɚКɚɪпɟнкоОПɊȿȾȿЛȿНИȿПɊОИЗȼОȾНОȽОȽИȾɊОКɋИПИɊɊОЛИНМОЧȿИЗɍЧȿНИȿȿȽОЭКɋКɊȿЦИИОɊȽȺНИЗМȺЛȺȻОɊȺɌОɊНЫɏɎɚɪмɚцияɮɚɪмɚколоɝияȻɭлɝɚкоɜɚКɚɪпɟнкоFor citation:Bulgakova E.A., Karpenko Yu.N., Yarygina T.I. DETERMINATION OF 3-HYDROXY-3-PYRROLINE-2-ONE IN URINE AND STUDY OF ITS EXCRETION FROM THE ORGANISM OF LABORATORY ANIMALS. DETERMINATION OF 3HYDROXYPYRROLINEONE IN URINE AND STUDY OF ITS EXCRETION FROM THE ORGANISM OF LABORATORY ANIMALSE.A. Bulgakova, Yu.N. Karpenko, T.I. YaryginaPerm State Pharmaceutical Academydisorders. The drugs of choice in the complex therapy in this case are nootropics. On the world market racetam group, i.e. derivatives of alpha-pyrrolidone, prevails among nootropics, and the derivatives have a wide spectrum of pharma-ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistrycological activity. Currently, this group continues to expand. By the employees of Perm State Pharmaceutical Acade-my (PSPA), ruled by Professor V.L. Gein, a new biologically active compound, a 3-pyrrolin-2-one derivative - KOH-1 was synthesized. This compound is at the preclinical research stage now. methods for determination of KOH-1 in urine by high performance liquid chromatography (HPLC), the study of excre-tion KOH-1 from the organism of laboratory animalswere carried out by using a liquid chromatograph LC-20 Prominence (Shimadzu, Japan) with a diode-array detector.The validation was carried out in accordance with the requirements for bioanalytical methods, in terms of selectivity, linearity, precision and accuracy. The study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g. The substance KOH-1 was administered once orally in a suspension of starch mucus at a dose As a result of the research, the method for determining the biologically active The data on daily excretion of KOH-1 in urine after a single oral administration to rats were obtained. The developed conditions for the chromatographic determination of KOH-1 in urine can be used in pharmacokinetic studies, both at the preclinical and clinical stages of the study of a potential drug. The data on excretion of KOH-1 will allow to determine the ways of excretion of the preparation, and also to select a rational dosage, to identify possible nootropics, KOH-1, high-performance liquid chromatography, validation, pharmacokineticsȼɜɟɞɟниɟИзɜɟɫɬночɬопɪɚкɬичɟɫкилюɛоɟзɚɛолɟɜɚниɟɫɬоɪоныцɟнɬɪɚльнойɫопɪоɜожɞɚɟɬɫякоɝниɬиɜныɯɫɬɪойɫɬɜкоɬоɪыɟпɪояɜляюɬɫяɫнижɟнииɜнимɚнияɭмɫɬɜɟннойɪɚɛоɬоɫпоɫоɛноɫɬиКоɝниɪɚɫɫɬɪойɫɬɜɚнɟɝɚɬиɜноɫкɚзыɜɚюɬɫякɚчɟɫɬɜɟпɚциɟнɬɚнɭжɞɚюɬɫякоɪɪɟкции [1]. ПɪɟпɚɪɚɬɚмиɫоɫɬɚɜɟкомплɟкɫнойɬɟɪɚпииɞɚнномяɜляюɬɫянооɬɪопынɚɫɬоящɟɟяɜляюɬɫяɟɞинɫɬɜɟннойɝɪɭппойɮɚɪмɚколоɝичɟɫкиɯɫɪɟɞɫɬɜɜыɪɚжɟннымнɟйɪомɟɬɚɛоличɟɫкиммиɪоɜомɪынкɟɫɪɟɞиɊиɫɭнокɋɬɪɭкɬɭɪнɚяɮоɪмɭлɚКОНɚцɟɬилɛɪомɮɟнилɝиɞɪокɫиɝиɞɪокɫипɪопилпиɪɪолиноɬɪопныɯпɪɟпɚɪɚɬоɜпɪɟоɛлɚɞɚɟɬɝɪɭппɚɪɚцɟɬɚмоɜпɪоизɜоɞныɯɚльɮɚпиɪɪолиɞонɚɯɚɪɚкɬɟɪизɭюɫпɟкɬɪомɮɚɪмɚколоɝичɟɫкойɚкɬиɜноɫɬинɚɫɬоящɟɟɝɪɭппɚпɪоɞолжɚɟɬɋоɬɪɭɞникɚмиПɟɪмɫкойɝоɫɭɞɚɪɫɬɜɟнɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмииПȽɎȺпоɞɪɭкоɜоɞɫɬɜомпɪоɮɟɫɫоɪɚȽɟйнɚɫинɬɟзиɪоɜɚноноɜоɟɛиолоɝичɟɫкиɚкɬиɜноɟɫоɟɞинɟниɟ [2], ɜоɞноɟ 3-пиɪɪолин ? КОНоɛлɚɞɚɜыɪɚжɟннымɚнɬиɚмнɟɫɬичɟɫкимɋɟйчɚɫɫоɟɞинɟниɟпɪоɯоɞиɬɫɬɚɞиюɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийȼнɟɞɪɟниɟпɪɟпɚɪɚɬоɜчɟɫкɭюпɪɚкɬикɭоɫɭщɟɫɬɜимоɞɟɬɚльнойɫпɟциɮичɟɫкойɮɚɪмɚколоɝичɟɫкойɚкɬиɜноɫɬиɛɟзопɚɫноɫɬиɫɬɚɞииэкɫпɟɪимɟнɬɚльныɯɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийɞоклиничɟɫкиɯɮɚɪмɚкокинɟɬичɟɫкиɯɞоɜɚнийяɜляɟɬɫяизɭчɟниɟпоɜɟɞɟнияпоɬɟнциɚльлɟкɚɪɫɬɜоɪɝɚнизмɟлɚɛоɪɚɬоɪныɯжиɜоɬныɯпɪоцɟɫɫоɜɜɫɚɫыɜɚнияɪɚɫпɪɟɞɟлɟниямɟɬɚɛолизмɚɜыɜɟɞɟния [3]. Изɭчɟниɟэкɫкɪɟцииɜɚжныйэɬɚпкоɬоɪыйпозɜоляɟɬɫкоɪоɫɬьэлиминɚциипоɬɟнциɚльныɯлɟкɚɪɫɬɜɫɜязиɚкɬɭɚяɜляюɬɫяиɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟɜыɫокочɭɜɫɬɜиɬɟльныɯмɟɬоɞикɛиолоɝичɟɫкиɚкɬиɜныɯɫоɟɞинɟнийлоɝичɟɫкиɯжиɞкоɫɬяɯчɚɫɬноɫɬимочɟɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯоɬɪопныɯпɪɟпɚɪɚɬоɜɝɪɭппыɪɚцɟɬɚмоɜиɫпользɭюɬɫямɟɬоɞыɝɚзожиɞкоɫɬнойɯɪомɚɬоɝɪɚɮии [4], ɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииɮлɭоɪимɟɬɪичɟɫким [5] мɚɫɫɫɟлɟкɬиɜнымɬиɪоɜɚниɟм [6-12]. ɫпоɫоɛɚпɪоɛопоɞɝоɬоɜмочиɚнɚлизɭɮизикоɯимичɟɫкиɯɫɜойɫɬɜлɟкɚɪɫɬɜɟнноɝоɜɟщɟɫɬɜɚɌɚкɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯнооɬɪопныɯɬоɜɚнɚлизɟмочииɫпользɭюɬпɪоɛопоɞɝоɬоɜкɭоɫноɜɟжиɞкоɫɬьжиɞкоɫɬнойэкɫɬɪɚкции [13, 14, пɪоɫɬоɟɪɚзɛɚɜлɟниɟɜоɞой [16]. пɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚнияпокɚзɚличɬоКОНɮɟкɬиɜноэкɫɬɪɚɝиɪɭɟɬɫямочи 3 ɮоɪмомɛолɟɟ 3 Цɟлью нɚшɟй ɪɚɛоɬыɪɚзɪɚɛоɬкɚмɟɬоPharmacy & Pharmacology V. 5 N 4, 2017опɪɟɞɟлɟнияКОНмочɟмɟɬоɞомɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииȼЭЖɏɬɚкжɟизɭчɟниɟэкɫкɪɟцииКОНоɪɝɚнизмɚɪɚɬоɪныɯжиɜоɬныɯМɚɬɟɪиɚлымɟɬоɞыɪɚɛоɬɟиɫпользоɜɚɫɭɛɫɬɚнциюКОНɫинɬɟзиɪоɜɚннɭюПȽɎȺɫооɬɜɟɬɫɬɜɭющɭюɬɪɟɛоɜɚниямпɪоɟкɬɚ [18], ɬɚкжɟɫлɟɞɭющиɟɪɟɚɝɟнɬыɚцɟɬониɬɪилgrade, Merckɯлоɪиɫɬоɜоɞоɪоɞнɚякиɫлоɬɚɪɚзɜɟ 8,3%, кɚлияɞиɝиɞɪоɮоɫɮɚɬɯлоɪоɮоɪмȼоɞɚпɪиɝоɬоɜлɟнияэлюɟнɬоɜполɭпомощьюочиɫɬкиɜоɞыSimplicity UV (Millipore, Merck).ИɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟмɟɬоɞикипɪоɜоɞииɫпользоɜɚниɟмжиɞкоɫɬноɝоɯɪомɚɬоɝɪɚɮɚLC-20 Prominence (Shimadzu, ɞиоɞномɚɞɟɬɟкɬоɪомɏɪомɚɬоɝɪɚɮичɟɫкɚяколон (250?4,6 кɚчɟɫɬɜɟпоɞɜижнойиɫпользоɜɚлиɫмɟɫьɚцɟɬониɬɪилɚɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7). ȾɟɬɟкɬиɪоɜɚпɪоɜоɞилиɜолныПɪоɛопоɞɝоɬоɜкɭмочиоɫɭщɟɫɬɜлялимɟɬоɞомжиɞкоɫɬьжиɞкоɫɬнойэкɫɬɪɚкцииɯлоɪоɮоɪмомэɬоɝопɪоɛиɪкɭпомɟщɚли 1 моɞɟльнойɫмɟɫипоɞкиɫляликиɫлоɬойɫɬоɜоɞоɪоɞнойɪɚзɜɟɞɟнной 8,3 % 3 ɭниɜɟɪɫɚльномɭинɞикɚɬоɪɭ (50 Ⱦɚлɟɟпɪоɜоɞилиɞɜɭкɪɚɬнɭюэкɫɬɪɚкциюɯлоɪоɮоɪмом 0,5 иɫпользɭяпɪоɛиɪочныйɜоɪɬɟкɫкɚжɞойэкɫɬɪɚкции ? 1 минɭɬɚОɛɪɚзоɜɚɜшɭюɫяэмɭльɫиюɪɚзɪɭшɚлицɟнɬɪиɮɭɝиɪоɜɚния 5000 ɬɟчɟниɟ 5 ОɪɝɚничɟɫкийпɟɪɟноɫиличɚшкɭɫɭɯойоɫɬɚɬокпоɫлɟɭɞɚлɟэкɫɬɪɚɝɟнɬɚɬокɟɬɟплоɝоɜозɞɭɯɚɪɚɫɬɜоɪялимɟɬɚнолɚИзɜлɟчɟнияɮильɬɪоɜɚличɟɪɟзɮильɬɪыɪɚзмɟɪом 5 ȼɚлиɞɚциюɪɚзɪɚɛоɬɚнноймɟɬоɞикипɪоɜоɞиɫооɬɜɟɬɫɬɜииɬɪɟɛоɜɚниямипɪɟɞъяɜляɟмымиɛиоɚнɚлиɬичɟɫкиммɟɬоɞикɚмпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьлинɟйноɫɬьноɫɬьпɪɚɜильноɫɬь [ 19, 20, 21].ИɫɫлɟɞоɜɚниɟэкɫкɪɟцииКОНпɪоɜоɞилиɛɟлыɯкɪыɫɚɯɫɚмцɚɯмɚɫɫой 300-400 полɭчɟнныɯɜиɜɚɪияПȽɎȺɋɭɛɫɬɚнциюКОНɜɜоɞилиоɞнокɪɚɬнопɟɪоɪɚльноɫɭɫпɟнзиимɚльной 100 ɋɛоɪэкɫкɪɟɬоɜоɫɭщɟɫɬɜлялимɟɬɚɛоличɟɫкиɯклɟɬкɚɯɬɟчɟниɟ 24 поɫлɟɜɜɟɞɟнияКОНɊɟзɭльɬɚɬыоɛɫɭжɞɟниɟɍɫлоɜияɯɪомɚɬоɝɪɚɮиɪоɜɚнияɞɟɬɟкɬиɪоɜɚнияпɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚнияпокɚзɚлиэɮɮɟкɬиɜноɫɬьиɫпользоɜɚнияэлюɟнɬɚоɫноɜɟɚцɟɬониɬɪилɚɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7) ɚнɚлизɚпɪоизɜоɞныɯ 3-ɝиɞɪокɫипиɪɪолин [22]. поɞɜижноймɚкɫимɭмпоɝлощɟКОНɫоɫɬɚɜляɟɬ 324 чɬооɛɟɫпɟчиɜɚɟɬɜыɫокɭюɫɟлɟкɬиɜноɫɬьɟɝоопɪɟɞɟлɟнияɚнɚлизɟɬɚкиɯɫложныɯмноɝокомпонɟнɬныɯкɚкɜлɟчɟнияɛиолоɝичɟɫкиɯоɛъɟкɬоɜɍɫɬɚноɜлɟночɬоɭɞɟɪжиɜɚнияиɫɫлɟɞɭɟмоɝоɜɟщɟɫɬɜɚконцɟнɬɪɚцииɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7) ɫоɫɬɚɜɟэлюɟнɬɚɍɜɟличɟниɟɛɭɮɟɪноɝоɪɚɫɬɜоɪɚэлюɟнɬɟ 60 80 % пɪиɜоɞиɬɭɜɟличɟниюɭɞɟɪжиɜɚния 3 11 ɋмɟɫьɮоɫɮɚɬноɝо 7) ɚцɟɬониɬɪилɚɫооɬношɟнии 75:25 поɬокɟ 1 оɛɟɫпɟчилɚкоэɮɮициɟнɬɭɞɟɪжиɜɚнияКОНɯоɪошɟɟɪɚзɞɟлɟниɟɫоɫɟɞнимиɯɪомɚɬоɝɪɚɮичɟɫкимипикɚмиɞɚлɟɟиɫпользоɜɚлɚɫькɚчɟɫɬɜɟпоɞɜижнойɭɞɟɪжиɜɚнияКОНɫоɫɬɚɜило. ɊиɫɭнокɫпɟкɬɪКОНпоɞɜижнойɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological ChemistryмɟɬоɞикиȼɚлиɞɚцияɪɚзɪɚɛоɬɚнноймɟɬоɞикиколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏпɪоɜɟɞɟнɚпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьлинɟйноɫɬьпɪɟцизионноɫɬьɜильноɫɬьɫооɬɜɟɬɫɬɜиипɪɟɞъяɜляɟмымиɬɪɟɛоɜɚниямиoxicological ChemistryɋɟлɟкɬиɜноɫɬьмɟɬоɞикиɭɫɬɚноɜлɟнɚɚнɚлизɚизɜлɟчɟнийɯолоɫɬыɯмочиɬɚкжɟмоɞɟльныɯɫмɟɫɟймочиконцɟнɬɪɚКОН 20 ɯɪомɚɬоɝɪɚммɚɯизɜлɟчɟнийɯолоɫɬоɝонɚɛлюɞɚлоɫьпикоɜɭɞɟɪжиɜɚнияɫооɬɜɟɬɫɬɜɭющимɭɞɟɪжиɜɚнияКОНчɬоɫɜиɞɟɬɟльɫɬɜɭɟɬɫɟлɟкɬиɜноɫɬимɟɬоɞикиоцɟнкɟлинɟйноɫɬимɟɬоɞикипɪиɝоɬоɜлɟныпɪоɚнɚлизиɪоɜɚны 8 моɞɟльныɯɪɚɫɬɜоɪоɜмочикɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜконцɟнɬɪɚциɟйКОНɞиɚпɚзонɟ 0,5 125 ɍɪɚɜнɟниɟкɚлиɛɪоɜочноɝоɝɪɚɮикɚ Y = 2189*X. эɮɮициɟнɬкоɪɪɟляцииɫоɫɬɚɜил 0,99865, чɬопоɞɌɚɛлицɚОɬклонɟнияконцɟнɬɪɚцийкɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜɮɚкɬичɟɫкиɯзнɚчɟнийɮɚкɬ0,692,097,7925,150,283,3100,4125,5ɪɚɫɫчиɬ0,632,157,8422,9748,2381,46100,86128,84,%-8,72,875,0-8,48-3,92-2,20,462,66Ноɪмɚɛолɟɟ20% ɛолɟɟɊиɫɭнокɏɪомɚɬоɝɪɚммɚизɜлɟчɟнияɯолоɫɬоймочиɊиɫɭнокɏɪомɚɬоɝɪɚммɚизɜлɟчɟниямоɞɟльнойɫмɟɫимочиконцɟнɬɪɚциɟйКОНɬɜɟɪжɞɚɟɬлинɟйноɫɬьмɟɬоɞикиɭкɚзɚнномɞиɚпɚзоКɚлиɛɪоɜочныйпɪɟɞɫɬɚɜлɟнɪиɫɭнкɟ 5. ɬɚɛлицɟ 1 пɪɟɞɫɬɚɜлɟныɪɟзɭльɬɚɬыоɛɪɚɬноɝопɟɪɟɪɚɫчɟɬɚконцɟнɬɪɚцийкɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜполɭчɟнныɯиɫпользоɜɚниɟмкɚлиɛɪоɜочноɝоɝɪɚɮикɚPharmacy & Pharmacology V. 5 N 4, 2017ɊиɫɭнокКɚлиɛɪоɜочныйколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏЭкɫпɟɪимɟнɬɚльноɪɚɫɫчиɬɚнныɟконцɟнɬɪɚциикɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜпɪɟɜышɚюɬпɪɟɞɟлоɜноминɚльныɯчɬоɫооɬɜɟɬɫɬɜɭɟɬпɪиɟмлɟмоɫɬи6 моɞɟльныɯконɬɪолякɚчɟɫɬɜɚ 5 концɟнɬɪɚцийКОН 111,56 пɪиɝоɬоɜпоɞɬɜɟɪжɞɟнияпɪиɝоɞноɫɬимɟɬоɞикипɚɪɚмɟɬɪɚмпɪɟцизионноɫɬьпɪɚɜильноɫɬьПоɞɝоɬоɜкɭɚнɚлизɚоɫɭщɟɫɬɜлялиɫооɬɜɟɬɫɬɜииопиɫɚнноймɟɬоɞикойПɪɟцизионноɫɬьпɪɚɜильноɫɬьмɟɬоɞикиоцɟниɜɚлиɜɟличинɚмоɬноɫиɬɟльноɝоɫɬɚнɞɚɪɬноɝооɬклонɟния (RSD, %) оɬноɫиɬɟльнойпоɝɪɟшноɫɬиɫооɬɜɟɬɫɬɜɟнноМɟɬɪолоɝичɟɫкиɟɯɚɪɚкɬɟɪиɫɬикимɟɬоɞикипɪɟɞɫɬɚɜлɟныɬɚɛлицɟɌɚɛлицɚМɟɬɪолоɝичɟɫкиɟɯɚɪɚкɬɟɪиɫɬикиколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏКонцɟнɬɪɚцияКОНмоɞɟльнойɫмɟɫиконцɟнɬɪɚцияSDRSD, %0,560,64; 0,58; 0,66; 0,53; 0,600,04677,78177,143,363,12; 3,41; 3,90; 3,75; 3,570,33529,38576,2516,8016,87; 16,95; 17,42; 17,310,37232,15123,0462,7555,51; 57,65; 58,47; 57,761,43752,4890-7,95111,5698,57; 101,98; 102,53; 102,763,70753,6079-7,89Полɭчɟнныɟɪɟзɭльɬɚɬыконɬɪоляпɪɟɜышɚюɬɞопɭɫкɚɟмыɯɛиоɚнɚлиɬичɟɫкиɯмɟɬоɞикчɬоɫɜиɞɟɬɟльɫɬɜɭɟɬоɬɫɭɬɫɬɜиизнɚчимыɯмɚɬичɟɫкиɯɪɟзɭльɬɚɬɚɯɚнɚлизɚ [19, 20, ɎɚɪмɚкокинɟɬичɟɫкиɟиɫɫлɟɞоɜɚнияɬɚннɚямɟɬоɞикɚиɫпользоɜɚнɚпɪоɜɟɞɟнииɞоклиничɟɫкиɯɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнийэкɫкɪɟцииКОНлɚɛоɪɚɬоɪныɯжиɜоɬныɯЭкɫжиɜоɬныɯоɫɭщɟɫɬɜлялɫяɫооɬɜɟɬɫɬɜииɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistryпɪɚɜоɜыминоɪмɚмииɫпользоɜɚнияжиɜоɬныɯпɪоɜɟɞɟнииɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийoxicological ChemistryОпыɬ пɪоɜоɞилиɛɟлыɯɫɚɯɫɚмцɚɯмɚɫɫойполɭчɟнныɯɜиɜɚɪияПɟɪмɫкойɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмииЖиɜоɬныɟɫоɞɟɪжɚлиɫьɫɬɚционɚɪныɯɟɫɬɟɫɬɜɟнномɫɜɟɬоɜомɫɬɚнɞɚɪɬном 20 нɚчɚлɚэкɫпɟɪимɟнɬɚжиɜоɬныɯлишɚлиɋɭɛɫɬɚнциюКОНɜɜоɞилиоɞнокɪɚɬноɪɚльноɫɭɫпɟнзиикɪɚɯмɚльной 100 ɋɛоɪэкɫкɪɟɬоɜоɫɭщɟɫɬɜлялимɟɬɚɛоличɟɫкиɯклɟɬкɚɯɬɟчɟниɟ 24 поɫлɟɜɜɟɞɟнияКОНɊɟзɭльɬɚɬыколичɟɫɬɜɟнноɝоɚнɚлизɚКОНмочипɪɟɞɫɬɚɜлɟныɬɚɛлицɟɌɚɛлицɚɋɭɬочноɟɫоɞɟɪжɚниɟКОНмочɟоɞнокɪɚɬноɝоɜɜɟɞɟнияɞозɟМɚɫɫɚОɛъɟммочиɪɭжɟннɚяконцɟнɬɪɚцияɜɜɟɞɟнной320,01794,755,0400,01960,232,9370,02183,584,9340,014141,835,9350,01787,084,2340,02467,874,7 = 4,6%ɌɚкимиоɛɪɚзомпɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚниякɚзɚличɬопоɫлɟоɞнокɪɚɬноɝопɟɪоɪɚльноɝоɜɜɟкɪыɫɚмɫɭɛɫɬɚнцииКОН 100 мочойɫɭɬкиɫɪɟɞнɟмɜыɜоɞиɬɫяоколо 5 % ɜɟщɟɫɬɜɚнɟизмɟнномЗɚключɟниɟɊɚзɪɚɛоɬɚнɚмɟɬоɞикɚколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟɜключɚющɚяɫɟɛяжиɞкоɫɬьжиɞкоɫɬнɭюэкɫɬɪɚкциюɚнɚлиɬɚпоɫлɟɞɭющимɟɝоопɪɟɞɟлɟниɟммɟɬоɞомȼЭЖɏɜɚлиɞɚционнойɭɫɬɚноɜлɟнɚлɟкɬиɜноɫɬьлинɟйноɫɬьпɪɚɜильноɫɬьонноɫɬьмɟɬоɞикиМɟɬоɞикɚиɫпользоɜɚнɚɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯизɭчɟнииэкɫкɪɟцииКОНмочойлɚɛоɪɚɬоɪныɯжиɜоɬПокɚзɚночɬопоɫлɟоɞнокɪɚɬноɝопɟɪоɪɚльноɝоɜɜɟɞɟниякɪыɫɚмɫɭɛɫɬɚнцииКОН 100 мочойɫɭɬкиɫɪɟɞнɟмɜыɜоɞиɬɫяоколо 5% ɜɟщɟɫɬɜɚнɟизмɟнномIntroduction.decrease in memory, attention and mental performance. Cognitive disorders adversely affect the quality of life of the patient and need correction [1]. The drugs of choice in the complex therapy in this case are nootropics. Cur-rently, they are the only group of pharmacological agents with a pronounced neurometabolic effect. On the world have a wide spectrum of pharmacological activity.Cur-rently, this group continues to expand. By the employees of Perm State Pharmaceutical Academy (PSPA), ruled by Professor V.L. Gein, a new biologically active compound .L. Gein, a new biologically active compound ()synthesized.This compound is at the preclinical research stage now. Pharmacy & Pharmacology V. 5 N 4, 2017tice is feasible only when studying a detailed assessment c pharmacological activity and safety at the stage of experimental (preclinical) studies. The purpose of ior of potential drugs in the body of laboratory animals, i.e. the processes of absorption, distribution, metabolism and excretion [3]. The study of excretion is an important stage of the preclinical, which allows estimating the rate of elimination of potential drugs. In this connection, studies termination of biologically active compounds in biological uids, particularly in urine, are relevant. performance liquid chromatography with ? uorimetric [5] and mass selective detection [6-12] are used. The drug substance. Thus, for pharmacokinetic studies of Thus, for pharmacokinetic studies of of the sample with water [16]. The previous studies have shown that KOH-1 is effectively extracted from urine at fectively extracted from urine at The aim of this work was working out methods for determination of KOH-1 in urine by high performance liquid chromatography (HPLC), the study of excretion of KOH-1 from the organism of laboratory animalsin PSPA and corresponding to the requirements of the and corresponding to the requirements of the also the following reagents: acetonitrile (HPLC grade, Merckdrogen phosphate (cp), chloroform (cp). The water for UV water puri cation system (Millipore, Merck).LC-20 Prominence (Shi-madzu, Japan) with a diode-array detector,graphic column Luna 5uC18 (2) 100A (250 ? 4.6 mm, Phenomenex). A mixture of acetonitrile and phosphate buffer (pH 7) was used as the mobile phase. The detec-traction with chloroform. To do this, 1 ml of a model ed with l). Then double extraction with tube vortex. The time of each extraction was 1 minute. at 5000 rpm for 5 minutes. The organic layer was trans-solved in 1 ml of methanol. The extracts were ltered lters with a pore size lters with a pore size The validation of the developed method was carried out in accordance with modern requirements for bioan-alytical methods, in terms of selectivity, linearity, preci-, preci-The study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g, ob-tained from the vivarium of PSPA. The substance KOH-1 Chromatography and de-The previous studies have shown the effectiveness of using the eluent on the basis of ace-tonitrile and phosphate buffer (pH 7) for the analysis of 3-hydroxy-3-pyrrolin-2-one derivatives [22]. In this mobile phase, the maximum absorption of KOH-1 is 324 nm (Fig. 2), which ensures high selectivity of its jects. It was found out that the retention time of the test substance strongly depends on the concentration of phosphate buffer (pH 7) in the composition of the eluent. Increasing the buffer solution in the eluent from 6% to 11 minutes. A mixture of phosphate buffer (pH 7) and ow of 1 ml / min pro-vided an acceptable KOH-1 retention factor, good sep-it was used as the mobile phase. The retention time of Validation of the developed urine by the HPLC-UV method was carried out in terms of selectivity, linearity, precision and accuracy in accor--The selectivity of the method was established by an-alyzing the extracts from ?blank? urine samples, as well as model urine mixtures with KOH-1 concentration of 20 μg / ml. The chromatograms of the extracts from the blank sample showed no peaks with retention time cor-prepared and analyzed. The equation of the calibration graph had the form Y = 2189 * X. The correlation coef- cient was 0.99865, which con rms the linearity of the technique in this range. The calibration graph is shown Table 1 shows the results of the reverse recalculation ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological ChemistryFigure 2 ? UV spectrum of KOH-1 in the mobile phasePharmacy & Pharmacology V. 5 N 4, 2017Table 1 0.692.097.7925.150.283.3100.4125.50.632.157.8422.9748.2381.46100.86128.84,%-8.72.875.0-8.48-3.92-2.20.462.6620, 21].6 model bio-samples (quality control samples) at 5 concentration levels of KOH-1 (0.56; 3.36; 16.80; 62.75 and 111.56 rm the suitabil-ity of the technique in terms of precision and accuracy. , %), respectively. Metrological characteristics of the method are presented in Table 2.Table 2 ? Metrological characteristics of the quantitative determination of KOH-1 in urine by HPLCKOH-1 in the model mixture, g / mlFound concentration, g / mlSDRSD, %0.560.64; 0.58; 0.66; 0.600.04677.78177.143.363.12; 3.41; 3.90; 3.570.33529.38576.2516.8016.87; 16.95; 17.42; 17.310.37232.15123.0462.7555.51; 57.65; 58.47; 57.761.43752.4890-7.95111.5698.57; 101.98; 102.763.70753.6079-7.89ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistry cant systematic errors in the results of cant systematic errors in the results of Pharmacokinetic studies. The developed technique was used for preclinical pharmacokinetic studies on KOH-1 excretion in laboratory animals. An animal ex-An animal ex-Study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g, obtained from the vivarium of PSPA. The animals were kept in stationary conditions in natural light mode on a standard diet. 20 hours before the experiment the animals were deprived of food. The sub-stance KOH-1 was administered once orally in suspension creta was performed in metabolic cages for 24 hours after administration of KOH-1. The results of quantitative anal-ysis of KOH-1 in urine samples are presented in Table 3.Table 3 ? Daily content of KOH-1 in the urine of rats after a single oral administration Rat weight, gVolume of urine, ml320.01794.755.0400.01960.232.9370.02183.584.9340.014141.835.9350.01787.084.2340.02467.874.7 = 4.6 %gle oral administration of KOH-1 to the rats in the dose of 100 mg/kg, about 5% of the substance on changed form. subsequent determination by HPLC / UV.The selectivity, linearity, accuracy and precision of the methodology were established by the validation The technique has been successfully used cretion in urine in laboratory animals. It is shown that after a single oral administration of KOH-1 to the rats in the dose of 100 mg/kg, about 5% of the substance changed form. ȻиɛлиоɝɪɚɮичɟɫкийɍшкɚлоɜɚɍшкɚлоɜɚɎȺɊМȺКОɌȿɊȺПИЯКОȽНИɌИȼНЫɏНȺɊɍШȿНИЙɊȺЗЛИЧНОȽОȽȿНȿЗȺɋОɋɌОЯНИȿПȿɊɋПȿКɌИȼНЫȿНȺПɊȺȼЛȿНИЯ //ɊМЖ 22. КоллɚȺНɌИȺМНȿɋɌИЧȿɋКОȿПɊОИЗȼОȾНЫɏɊЯȾȺ 3-ȽИȾɊОКПИɊɊОЛИНЭкɫпɟɪимɟнɬɚльнɚяклиничɟɫкɚяɮɚɪмɚколоɝияМɟньшикоɜɚПɟчɟнкинɚȻɟɪɟзɚОɋОȻȿННОɋɌИИɋɋЛȿȾОȼȺИННОȼȺЦИОННЫɏЛȿКȺɊɋɌȼȿННЫɏПɊȿПȺɊȺɌОȼКОɊОɌКОȿНɚɭчпɪоизɜоɞɫɬɜжɭɪнɚлɊɚзɪɚɛоɬкɚɪɟɝиɫɬɪɚцияɞɚɬɚ.) ȺнɬоноɜɚПɪокопоɜȺɯɚпкинɚȻɟɪлянɞКОЛИЧȿɋɌȼȿННЫЙɎȿНОɌɊОȻИОЛОȽИЧȿɋКИɏОȻЪȿКɌȺɏМȿɌОȾОМȽȺЗОЖИȾКОɋɌНОЙɏɊОМȺɌОȽɊȺɎИИ // ɮɚɪмжɭɪнSimpson R.C., Boppana V.K., Hwang B.Y., Rhodes G.R. DETERMINATION OF OXIRACETAM IN HUMAN PLASMA BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH Journal of Chromatography. 1993. No. 631 (1-2). P. 227?232. Zhang J., Liang J., Tian Y., Zhang Z., Chen Y. 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COMPARATIVE PHARMACOKINETIC STUDIES OF RACEMIC OXIRACETAM AND ITS PURE ENANTIOMERS AFTER ORAL ADMINISTRATION IN RATS BY A STEREOSELECTIVE HPLC METHOD // . 2015. No. 111. P. 153-158. DOI: 10.1016/j.jpba.2015.03.039Son J., Lee J., Lee M., Lee E., Lee K.T., La S., Kim D.H. RAPID QUANTITATIVE ANALYSIS OF OXIRACETAM IN HUMAN PLASMA BY LIQUID CHROMATOGRAPHY/ELECTROSPRAY TANDEM MASS SPECTROMETRY // . 2004. No. 36 (1). P. 183?187. Wan X., Wang H., Ma P., Xi L., Sun J., He Z., Zhang X., Liu X. SIMULTANEOUS DETERMINATION OF OXIRACETAM AND ITS DEGRADED SUBSTANCE IN RAT PLASMA BY HPLC-MS/MS AND ITS APPLICATION TO PHARMACOKINETIC STUDY AFTER A SINGLE HIGH-DOSE INTRAVENOUS ADMINISTRATION // Journal of chromatography B analytical technologies in the biomedical and life sciences.2014. No. 969. P. 95-100. DOI: 10.1016/j.jchromb.2014.07.041 Wang X., Zhu J., Xu R., Yang X., Wu H., Lin D., Ye F., Hu L. DETERMINATION OF PIRACETAM IN RAT PLASMA BY LC-MS/MS AND ITS APPLICATION TO PHARMACOKINETICS // Biomedical Chromatography. 2010. No. 24(10). P. 1108?1112. DOI: 10.1002/bmc.1412.ПɪокопоɜКоɬлоɜɚȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИɌȿɌɊȺМȿЗИНȺɮɚɪмжɭɪнПɪокопоɜКоɫɬɟɛɟлоɜȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИȺЛЬȻИКȺɊȺОɊȽȺНИЗМȺɮɚɪмжɭɪнȺнɬоноɜɚПɪокопоɜȺɯɚпкинɚȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИПɊȿПȺɊȺɌȺɎȿНОɌɊОПИЛОɊȽȺНИЗМȺ // ɮɚɪмжɭɪн 11. Farhan A.S., Nawab S., Nighat S., Alisha W.S., Ahmad M.,Mehjebeen, Naseem H. DEVELOPMENT OF NEW METHOD FOR SIMULTANEOUS ANALYSIS OF PIRACETAM AND LEVETIRACETAM IN PHARMACEUTICALS AND BIOLOGICAL FLUIDS: APPLICATION IN STABILITY STUDIES // Research International. 2014. Vol. 2014. Article ID 758283, 8 pages. DOI:10.1155/2014/758283ȻɭлɝɚкоɜɚКɚɪпɟнкоȼЫȻОɊɍɋЛОȼИЙИЗȼЛȿЧȿНИЯȻИОЛОȽИЧȿɋКИПɊОИЗȼОȾНЫɏ 3-ПИɊɊОЛИНМОЧИ // ИнноɜɚционнɚянɚɭкɚмɟжɞɭнɚɪоɞнɚɭчныйжɭɪнɚлɌомКляшɟɜɚ., ȽɟйнОɞɟɝоɜɚɋɚɬɬɚɪоɜɚКɚɪпɟнкоɊȺЗɊȺȻОɌКȺɌОȾОȼКȺЧȿɋɌȼȺɋɍȻɋɌȺНЦИИНОȼОȽОȻИОЛОȽИЧȿɋКИȺКɌИȼНОȽОКОНɎɚɪмɚцияand Drug Administration, Center for Drug Evolution and Research (CDER). U.S. Government Printing Of ce. Washington, DC, 2001. 25 p.Guideline on validation of bioanalytical methods (draft) / European Medicines Agency. Committee for medicinal Ɋɟшɟниɟɋоɜɟɬɚȿɜɪɚзийɫкойэкономичɟɫкойкомиɫɫии 03.11.2016 85 ?ɭɬɜɟɪжɞɟнииɜɟɞɟнияиɫɫлɟɞоɜɚнийɛиоэкɜиɜɚлɟнɬноɫɬилɟкɚɪɫɬɜɟнныɯпɪɟпɚɪɚɬоɜɪɚмкɚɯȿɜɪɚзийɫкоɝоэкономичɟɫкоɝоМɚнɬɭɪоɜКɚɪпɟнкоɊɚзɪɚɛоɬкɚопɪɟɞɟлɟнияɛиолоɝичɟɫкиɚкɬиɜноɝоɫоɟɞинɟниямɟɬоɞомȼЭЖɏɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚний // ɊɚзɪɚɛоɬкɚиɫɫлɟɞоɜɚниɟмɚɪкɟɬинɝноɜойɮɚɪмɚцɟɜɬичɟɫкойпɪоɞɭкциинɚɭчПяɬиɝоɪɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияПяɬиɝоɪɫкɭɬɜɟɪжɞɟниилɚɛоɪɚɬоɪнойпɪɚкɬикипɪикɚзМиниɫɬɟɪɫɬɜɚзɞɪɚɜооɯɪɚнɟнияɫоциɚльноɝоɊоɫɫийɫкойɎɟɞɟɪɚции 23 ɚɜɝɭɫɬɚ 2010 . URL: http://www.consultant.ru/document/cons_doc_LAW_105953/ (ɞɚɬɚ: 11.01.2017 ReferencesUshkalova E.A., Ushkalova A.V. FARMAKOTERAPIJA KOGNITIVNYH NARUSHENIJ RAZLICHNOGO GENEZA: SOVREMENNOE SOSTOJANIE I PERSPEKTIVNYE NAPRAVLENIJA [PHARMACOTHERA-PY OF COGNITIVE DISTURBANCES OF VARIOUS GENESIS: MODERN STATE AND PERSPECTIVE AND PERSPECTIVE 2014. N 22. P.1613. (In Russ.)Shuklina N.S., Kolla V.Je. 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(in Russ.)of the Ministry of Health and Social Development of the Russian Federation of August 23, 2010 708-n]. URL: http://www.consultant.ru/document/cons_doc_LAW_105953/ (access data: 11.01.2017). (in Russ.) ict of interest ict of interest.Candidate of Sciences (Pharmacy), Associate Professor of the Department of Toxicological Chemistry, Perm State Pharmaceutical Academy. Research interests: development and valida-tion of bioanalytical techniques, research in the eld of pharmacokinetic studies, high-performance liquid chro-matography. E-mail: karpenko_pfa @ mail.ruYarygina Tatyana Ivanovna (Pharmacy), Professor of the Department of Pharmaceu-tical Chemistry, Faculty of Full-time Studies, Perm State Pharmaceutical Academy. Research interests: develop-ment of methods for quality control and standardization of biologically active compounds from gamma-aminobu-tyric acid and 3-hydroxy-3-pyrrolin-2-one groups; devel-opment of new and improvement of known spectrophoto-Bulgakova Evgenia Aleksandrovna the Department of Toxicological Chemistry, Perm State Pharmaceutical Academy. Research interests: develop-ment and validation of bioanalytical techniques, phar-macokinetic studies, high-performance liquid chroma-tography. E-mail: bugakova_pfa @ mail.ruКонɮликɬинɬɟɪɟɫоɜȺɜɬоɪызɚяɜляюɬоɬɫɭɬɫɬɜииконɮликɬɚинɬɟɪɟɫоɜȺɜɬоɪыКɚɪпɟнкоНиколɚɟɜнɚ ? кɚнɞиɞɚɬмɚцɟɜɬичɟɫкиɯнɚɭкɞоцɟнɬкɚɮɟɞɪы ɬокɫиколоɝичɟɫкой, ПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚɜɚлиɞɚцияɛиоɚнɚлиɬичɟɫкиɯмɟɬоɞикиɫɫлɟɞоɜɚнияоɛлɚɫɬиɮɚɪмɚцɟɜɬичɟɫкоɝоɬокɫиколоɝичɟɫкоɝоɮɚɪмɚкокинɟɬичɟиɫɫлɟɞоɜɚнияɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоɝɪɚɮия. E-mail: karpenko_pfa@ mail.ruɌɚɬьянɚИɜɚноɜнɚ ? ɞокɬоɪɮɚɪмɚцɟɜɬичɟɫкиɯнɚɭкпɪоɮɟɫɫоɪкɚɮɟɞɪыɮɚɪмɚцɟɜɬичɟɫкойɮɚкɭльɬɟɬɚочноɝооɛɭчɟнияПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚмɟɬоɞоɜконɬɪолякɚчɟɫɬɜɚɫɬɚнɞɚɪɬизɚцииɛиолоɝичɟɫкиɚкɬиɜныɯɫоɟɞинɟнийɝɪɭпппɪоизɜоɞныɯминомɚɫлянойкиɫлоɬы 3-ɝиɞɪокɫипиɪɪолинɪɚзɪɚɛоɬкɚɫоɜɟɪшɟнɫɬɜоɜɚниɟизɜɟɫɬɫпɟкɬɪоɮоɬомɟɬɪичɟɫкиɯмɟɬоɞиклɟкɚɪɫɬɜɟнныɯɫɪɟɞɫɬɜȻɭлɝɚкоɜɚȺлɟкɫɚнɞɪоɜнɚ ? кɚɮɟɞɪыɬокɫиколоɝичɟɫкойПɟɪмɫкɚяɝоɫɭɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚɜɚлиɞɚциялиɬичɟɫкиɯмɟɬоɞикɮɚɪмɚкокинɟɬичɟɫкиɟиɫɫлɟɞоɜɚнияɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоПоɫɬɭпилɚɪɟɞɚкциюПɪиняɬɚпɟчɚɬиPharmacy & Pharmacology V. 5 N 4, 2017ɍȾКОʿˀʫʪʫЛʫʻʰʫʿˀОʰʯʦОʪʻОʧОͳʧʰʪˀОКˁʰͳͳʿʰˀˀОЛʰʻͳͳОʻʤʰʯ˄ЧʫʻʰʫʫʧОˑКˁКˀʫˉʰʰОˀʧʤʻʰʯʺʤЛʤʥОˀʤ˃ОˀʻˏˈʮʰʦО˃ʻˏˈȻɭлɝɚкоɜɚКɚɪпɟнкоɎȽȻОɍПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияМинзɞɪɚɜɚɊоɫɫииɊоɫɫияПɟɪмьПолɟɜɚяИзɜɟɫɬнопɪɚкɬичɟɫкилюɛоɟзɚɛолɟɜɚниɟцɟнɬɪɚльнойɫиɫɬɟмыɫопɪоɜожɞɚɟɬɫяɪɚзɜиɬиɟмкоɝниɬиɜныɯПɪɟпɚɪɚɬɚмиɜыɛоɪɚɫоɫɬɚɜɟкомплɟкɫнойɞɚнномɫлɭчɚɟмиɪоɜомɪынкɟɫɪɟɞипɪɟоɛлɚɞɚɟɬɝɪɭппɚɪɚцɟɬɚпɪоизɜоɞныɯпиɪɪолиɞонɚɯɚɪɚкɬɟɪизɭющɚяɫяɫпɟкɬɪомɮɚɪмɚколоɝичɟɫкойɚкɬиɜнонɚɫɬоящɟɟɜɪɟмяɝɪɭппɚпɪоɞолжɚɟɬɪɚɫшиɪяɬьɫяɋоɬɪɭɞникɚмиПɟɪмɫкойɝоɫɭɞɚɪɫɬɜɟннойɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмиипоɞɪɭкоɜоɞɫɬɜомпɪоɮɟɫɫоɪɚȽɟйнɚɛылоɫинɬɟзиɪоɜɚноноɜоɟɛиолоɝичɟɚкɬиɜноɟɫоɟɞинɟниɟпɪоизɜоɞноɟ 3-ɝиɞɪокɫипиɪɪолин ? КОНкоɬоɪоɟɫɟйчɚɫпɪоɯоɞиɬэɬɚпɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийЦɟльюнɚɫɬоящɟйɪɚɛоɬыяɜилɚɫьɪɚзɪɚɛоɬкɚмɟɬоɞикиопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииȼЭЖɏɬɚкжɟизɭчɟниɟэкɫкɪɟцииКОНоɪɝɚнизмɚлɚɛоɪɚɬоɪныɯжиɜоɬныɯМɚɬɟɪиɚлымɟɬоɞыИɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟмɟɬоɞикипɪоɜоɞилииɫпользоɜɚниɟмжиɞкоɫɬноɝоɯɪомɚɬоɝɪɚɮɚ LC-20 Prominence (Shimadzu, ɞиоɞномɚɞɟɬɟкɬоɪомоɫɭщɟɫɬɜлялиɫооɬɜɟɬɫɬɜииɬɪɟɛоɜɚниямипɪɟɞъяɜляɟмымиɚнɚлиɬичɟɫкиммɟɬоɞикɚмпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьЭкɫкɪɟциюКОНизɭчɚлиɛɟлыɯнɟлинɟйныɯкɪыɫɚɯмɚɫɫой 300?400 поɫлɟоɞнокɪɚɬноɝоɜɜɟɞɟнияɞозɟ 100 ɊɟзɭльɬɚɬыоɛɫɭжɞɟниɟɪɟзɭльɬɚɬɟиɫɫлɟɞоɜɚнийɪɚзɪɚɛоɬɚнɚмɟɬоɞикɚопɪɟɞɟлɟнияɛиолоɝичɟɫкиɚкɬиɜноɝоɫоɟɞинɟнияКОНмочɟПɪоɜɟɞɟннɚяɜɚлиɞɚцияпокɚзɚлɚпɪиɝоɞɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнийПолɭчɟныɫɭɬочномɭɜыɜɟɞɟниюКОНмочойпоɫлɟоɞнокɪɚɬноɝоɜɜɟɞɟниякɪыɫɚмЗɚключɟниɟɊɚзɪɚɛоɬɚнныɟɭɫлоɜияɯɪомɚɬоɝɪɚɮичɟɫкоɝоопɪɟɞɟлɟнияКОНмочɟиɫпользоɜɚныɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯкɚкɞоклиничɟɫкомɬɚкклиничɟɫкомэɬɚпɚɯизɭчɟниялɟкɚɪɫɬɜɟнноɝоɫɪɟɞɫɬɜɚэкɫкɪɟцииКОНпозɜоляɬопɪɟɞɟлиɬьɜыɜɟɞɟнияпɪɟпɚɪɚɬɚɬɚкжɟпоɞоɛɪɚɬьɞозиɜозможныɟпɪоɬиɜопокɚзɚнияКлючɟɜыɟɫлоɜɚКОНɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоɝɪɚɮияɜɚлиɞɚциямɚкокинɟɬикɚциɬиɪоɜɚнияȻɭлɝɚкоɜɚКɚɪпɟнкоОПɊȿȾȿЛȿНИȿПɊОИЗȼОȾНОȽОȽИȾɊОКɋИПИɊɊОЛИНМОЧȿИЗɍЧȿНИȿȿȽОЭКɋКɊȿЦИИОɊȽȺНИЗМȺЛȺȻОɊȺɌОɊНЫɏɎɚɪмɚцияɮɚɪмɚколоɝияȻɭлɝɚкоɜɚКɚɪпɟнкоFor citation:Bulgakova E.A., Karpenko Yu.N., Yarygina T.I. DETERMINATION OF 3-HYDROXY-3-PYRROLINE-2-ONE IN URINE AND STUDY OF ITS EXCRETION FROM THE ORGANISM OF LABORATORY ANIMALS. DETERMINATION OF 3HYDROXYPYRROLINEONE IN URINE AND STUDY OF ITS EXCRETION FROM THE ORGANISM OF LABORATORY ANIMALSE.A. Bulgakova, Yu.N. Karpenko, T.I. YaryginaPerm State Pharmaceutical Academydisorders. The drugs of choice in the complex therapy in this case are nootropics. On the world market racetam group, i.e. derivatives of alpha-pyrrolidone, prevails among nootropics, and the derivatives have a wide spectrum of pharma-ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistrycological activity. Currently, this group continues to expand. By the employees of Perm State Pharmaceutical Acade-my (PSPA), ruled by Professor V.L. Gein, a new biologically active compound, a 3-pyrrolin-2-one derivative - KOH-1 was synthesized. This compound is at the preclinical research stage now. methods for determination of KOH-1 in urine by high performance liquid chromatography (HPLC), the study of excre-tion KOH-1 from the organism of laboratory animalswere carried out by using a liquid chromatograph LC-20 Prominence (Shimadzu, Japan) with a diode-array detector.The validation was carried out in accordance with the requirements for bioanalytical methods, in terms of selectivity, linearity, precision and accuracy. The study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g. The substance KOH-1 was administered once orally in a suspension of starch mucus at a dose As a result of the research, the method for determining the biologically active The data on daily excretion of KOH-1 in urine after a single oral administration to rats were obtained. The developed conditions for the chromatographic determination of KOH-1 in urine can be used in pharmacokinetic studies, both at the preclinical and clinical stages of the study of a potential drug. The data on excretion of KOH-1 will allow to determine the ways of excretion of the preparation, and also to select a rational dosage, to identify possible nootropics, KOH-1, high-performance liquid chromatography, validation, pharmacokineticsȼɜɟɞɟниɟИзɜɟɫɬночɬопɪɚкɬичɟɫкилюɛоɟзɚɛолɟɜɚниɟɫɬоɪоныцɟнɬɪɚльнойɫопɪоɜожɞɚɟɬɫякоɝниɬиɜныɯɫɬɪойɫɬɜкоɬоɪыɟпɪояɜляюɬɫяɫнижɟнииɜнимɚнияɭмɫɬɜɟннойɪɚɛоɬоɫпоɫоɛноɫɬиКоɝниɪɚɫɫɬɪойɫɬɜɚнɟɝɚɬиɜноɫкɚзыɜɚюɬɫякɚчɟɫɬɜɟпɚциɟнɬɚнɭжɞɚюɬɫякоɪɪɟкции [1]. ПɪɟпɚɪɚɬɚмиɫоɫɬɚɜɟкомплɟкɫнойɬɟɪɚпииɞɚнномяɜляюɬɫянооɬɪопынɚɫɬоящɟɟяɜляюɬɫяɟɞинɫɬɜɟннойɝɪɭппойɮɚɪмɚколоɝичɟɫкиɯɫɪɟɞɫɬɜɜыɪɚжɟннымнɟйɪомɟɬɚɛоличɟɫкиммиɪоɜомɪынкɟɫɪɟɞиɊиɫɭнокɋɬɪɭкɬɭɪнɚяɮоɪмɭлɚКОНɚцɟɬилɛɪомɮɟнилɝиɞɪокɫиɝиɞɪокɫипɪопилпиɪɪолиноɬɪопныɯпɪɟпɚɪɚɬоɜпɪɟоɛлɚɞɚɟɬɝɪɭппɚɪɚцɟɬɚмоɜпɪоизɜоɞныɯɚльɮɚпиɪɪолиɞонɚɯɚɪɚкɬɟɪизɭюɫпɟкɬɪомɮɚɪмɚколоɝичɟɫкойɚкɬиɜноɫɬинɚɫɬоящɟɟɝɪɭппɚпɪоɞолжɚɟɬɋоɬɪɭɞникɚмиПɟɪмɫкойɝоɫɭɞɚɪɫɬɜɟнɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмииПȽɎȺпоɞɪɭкоɜоɞɫɬɜомпɪоɮɟɫɫоɪɚȽɟйнɚɫинɬɟзиɪоɜɚноноɜоɟɛиолоɝичɟɫкиɚкɬиɜноɟɫоɟɞинɟниɟ [2], ɜоɞноɟ 3-пиɪɪолин ? КОНоɛлɚɞɚɜыɪɚжɟннымɚнɬиɚмнɟɫɬичɟɫкимɋɟйчɚɫɫоɟɞинɟниɟпɪоɯоɞиɬɫɬɚɞиюɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийȼнɟɞɪɟниɟпɪɟпɚɪɚɬоɜчɟɫкɭюпɪɚкɬикɭоɫɭщɟɫɬɜимоɞɟɬɚльнойɫпɟциɮичɟɫкойɮɚɪмɚколоɝичɟɫкойɚкɬиɜноɫɬиɛɟзопɚɫноɫɬиɫɬɚɞииэкɫпɟɪимɟнɬɚльныɯɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийɞоклиничɟɫкиɯɮɚɪмɚкокинɟɬичɟɫкиɯɞоɜɚнийяɜляɟɬɫяизɭчɟниɟпоɜɟɞɟнияпоɬɟнциɚльлɟкɚɪɫɬɜоɪɝɚнизмɟлɚɛоɪɚɬоɪныɯжиɜоɬныɯпɪоцɟɫɫоɜɜɫɚɫыɜɚнияɪɚɫпɪɟɞɟлɟниямɟɬɚɛолизмɚɜыɜɟɞɟния [3]. Изɭчɟниɟэкɫкɪɟцииɜɚжныйэɬɚпкоɬоɪыйпозɜоляɟɬɫкоɪоɫɬьэлиминɚциипоɬɟнциɚльныɯлɟкɚɪɫɬɜɫɜязиɚкɬɭɚяɜляюɬɫяиɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟɜыɫокочɭɜɫɬɜиɬɟльныɯмɟɬоɞикɛиолоɝичɟɫкиɚкɬиɜныɯɫоɟɞинɟнийлоɝичɟɫкиɯжиɞкоɫɬяɯчɚɫɬноɫɬимочɟɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯоɬɪопныɯпɪɟпɚɪɚɬоɜɝɪɭппыɪɚцɟɬɚмоɜиɫпользɭюɬɫямɟɬоɞыɝɚзожиɞкоɫɬнойɯɪомɚɬоɝɪɚɮии [4], ɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииɮлɭоɪимɟɬɪичɟɫким [5] мɚɫɫɫɟлɟкɬиɜнымɬиɪоɜɚниɟм [6-12]. ɫпоɫоɛɚпɪоɛопоɞɝоɬоɜмочиɚнɚлизɭɮизикоɯимичɟɫкиɯɫɜойɫɬɜлɟкɚɪɫɬɜɟнноɝоɜɟщɟɫɬɜɚɌɚкɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯнооɬɪопныɯɬоɜɚнɚлизɟмочииɫпользɭюɬпɪоɛопоɞɝоɬоɜкɭоɫноɜɟжиɞкоɫɬьжиɞкоɫɬнойэкɫɬɪɚкции [13, 14, пɪоɫɬоɟɪɚзɛɚɜлɟниɟɜоɞой [16]. пɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚнияпокɚзɚличɬоКОНɮɟкɬиɜноэкɫɬɪɚɝиɪɭɟɬɫямочи 3 ɮоɪмомɛолɟɟ 3 Цɟлью нɚшɟй ɪɚɛоɬыɪɚзɪɚɛоɬкɚмɟɬоPharmacy & Pharmacology V. 5 N 4, 2017опɪɟɞɟлɟнияКОНмочɟмɟɬоɞомɜыɫокоэɮɮɟкɬиɜнойжиɞкоɫɬнойɯɪомɚɬоɝɪɚɮииȼЭЖɏɬɚкжɟизɭчɟниɟэкɫкɪɟцииКОНоɪɝɚнизмɚɪɚɬоɪныɯжиɜоɬныɯМɚɬɟɪиɚлымɟɬоɞыɪɚɛоɬɟиɫпользоɜɚɫɭɛɫɬɚнциюКОНɫинɬɟзиɪоɜɚннɭюПȽɎȺɫооɬɜɟɬɫɬɜɭющɭюɬɪɟɛоɜɚниямпɪоɟкɬɚ [18], ɬɚкжɟɫлɟɞɭющиɟɪɟɚɝɟнɬыɚцɟɬониɬɪилgrade, Merckɯлоɪиɫɬоɜоɞоɪоɞнɚякиɫлоɬɚɪɚзɜɟ 8,3%, кɚлияɞиɝиɞɪоɮоɫɮɚɬɯлоɪоɮоɪмȼоɞɚпɪиɝоɬоɜлɟнияэлюɟнɬоɜполɭпомощьюочиɫɬкиɜоɞыSimplicity UV (Millipore, Merck).ИɫɫлɟɞоɜɚнияɪɚзɪɚɛоɬкɟмɟɬоɞикипɪоɜоɞииɫпользоɜɚниɟмжиɞкоɫɬноɝоɯɪомɚɬоɝɪɚɮɚLC-20 Prominence (Shimadzu, ɞиоɞномɚɞɟɬɟкɬоɪомɏɪомɚɬоɝɪɚɮичɟɫкɚяколон (250?4,6 кɚчɟɫɬɜɟпоɞɜижнойиɫпользоɜɚлиɫмɟɫьɚцɟɬониɬɪилɚɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7). ȾɟɬɟкɬиɪоɜɚпɪоɜоɞилиɜолныПɪоɛопоɞɝоɬоɜкɭмочиоɫɭщɟɫɬɜлялимɟɬоɞомжиɞкоɫɬьжиɞкоɫɬнойэкɫɬɪɚкцииɯлоɪоɮоɪмомэɬоɝопɪоɛиɪкɭпомɟщɚли 1 моɞɟльнойɫмɟɫипоɞкиɫляликиɫлоɬойɫɬоɜоɞоɪоɞнойɪɚзɜɟɞɟнной 8,3 % 3 ɭниɜɟɪɫɚльномɭинɞикɚɬоɪɭ (50 Ⱦɚлɟɟпɪоɜоɞилиɞɜɭкɪɚɬнɭюэкɫɬɪɚкциюɯлоɪоɮоɪмом 0,5 иɫпользɭяпɪоɛиɪочныйɜоɪɬɟкɫкɚжɞойэкɫɬɪɚкции ? 1 минɭɬɚОɛɪɚзоɜɚɜшɭюɫяэмɭльɫиюɪɚзɪɭшɚлицɟнɬɪиɮɭɝиɪоɜɚния 5000 ɬɟчɟниɟ 5 ОɪɝɚничɟɫкийпɟɪɟноɫиличɚшкɭɫɭɯойоɫɬɚɬокпоɫлɟɭɞɚлɟэкɫɬɪɚɝɟнɬɚɬокɟɬɟплоɝоɜозɞɭɯɚɪɚɫɬɜоɪялимɟɬɚнолɚИзɜлɟчɟнияɮильɬɪоɜɚличɟɪɟзɮильɬɪыɪɚзмɟɪом 5 ȼɚлиɞɚциюɪɚзɪɚɛоɬɚнноймɟɬоɞикипɪоɜоɞиɫооɬɜɟɬɫɬɜииɬɪɟɛоɜɚниямипɪɟɞъяɜляɟмымиɛиоɚнɚлиɬичɟɫкиммɟɬоɞикɚмпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьлинɟйноɫɬьноɫɬьпɪɚɜильноɫɬь [ 19, 20, 21].ИɫɫлɟɞоɜɚниɟэкɫкɪɟцииКОНпɪоɜоɞилиɛɟлыɯкɪыɫɚɯɫɚмцɚɯмɚɫɫой 300-400 полɭчɟнныɯɜиɜɚɪияПȽɎȺɋɭɛɫɬɚнциюКОНɜɜоɞилиоɞнокɪɚɬнопɟɪоɪɚльноɫɭɫпɟнзиимɚльной 100 ɋɛоɪэкɫкɪɟɬоɜоɫɭщɟɫɬɜлялимɟɬɚɛоличɟɫкиɯклɟɬкɚɯɬɟчɟниɟ 24 поɫлɟɜɜɟɞɟнияКОНɊɟзɭльɬɚɬыоɛɫɭжɞɟниɟɍɫлоɜияɯɪомɚɬоɝɪɚɮиɪоɜɚнияɞɟɬɟкɬиɪоɜɚнияпɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚнияпокɚзɚлиэɮɮɟкɬиɜноɫɬьиɫпользоɜɚнияэлюɟнɬɚоɫноɜɟɚцɟɬониɬɪилɚɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7) ɚнɚлизɚпɪоизɜоɞныɯ 3-ɝиɞɪокɫипиɪɪолин [22]. поɞɜижноймɚкɫимɭмпоɝлощɟКОНɫоɫɬɚɜляɟɬ 324 чɬооɛɟɫпɟчиɜɚɟɬɜыɫокɭюɫɟлɟкɬиɜноɫɬьɟɝоопɪɟɞɟлɟнияɚнɚлизɟɬɚкиɯɫложныɯмноɝокомпонɟнɬныɯкɚкɜлɟчɟнияɛиолоɝичɟɫкиɯоɛъɟкɬоɜɍɫɬɚноɜлɟночɬоɭɞɟɪжиɜɚнияиɫɫлɟɞɭɟмоɝоɜɟщɟɫɬɜɚконцɟнɬɪɚцииɮоɫɮɚɬноɝоɛɭɮɟɪɚ 7) ɫоɫɬɚɜɟэлюɟнɬɚɍɜɟличɟниɟɛɭɮɟɪноɝоɪɚɫɬɜоɪɚэлюɟнɬɟ 60 80 % пɪиɜоɞиɬɭɜɟличɟниюɭɞɟɪжиɜɚния 3 11 ɋмɟɫьɮоɫɮɚɬноɝо 7) ɚцɟɬониɬɪилɚɫооɬношɟнии 75:25 поɬокɟ 1 оɛɟɫпɟчилɚкоэɮɮициɟнɬɭɞɟɪжиɜɚнияКОНɯоɪошɟɟɪɚзɞɟлɟниɟɫоɫɟɞнимиɯɪомɚɬоɝɪɚɮичɟɫкимипикɚмиɞɚлɟɟиɫпользоɜɚлɚɫькɚчɟɫɬɜɟпоɞɜижнойɭɞɟɪжиɜɚнияКОНɫоɫɬɚɜило. ɊиɫɭнокɫпɟкɬɪКОНпоɞɜижнойɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological ChemistryмɟɬоɞикиȼɚлиɞɚцияɪɚзɪɚɛоɬɚнноймɟɬоɞикиколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏпɪоɜɟɞɟнɚпокɚзɚɬɟлямɫɟлɟкɬиɜноɫɬьлинɟйноɫɬьпɪɟцизионноɫɬьɜильноɫɬьɫооɬɜɟɬɫɬɜиипɪɟɞъяɜляɟмымиɬɪɟɛоɜɚниямиoxicological ChemistryɋɟлɟкɬиɜноɫɬьмɟɬоɞикиɭɫɬɚноɜлɟнɚɚнɚлизɚизɜлɟчɟнийɯолоɫɬыɯмочиɬɚкжɟмоɞɟльныɯɫмɟɫɟймочиконцɟнɬɪɚКОН 20 ɯɪомɚɬоɝɪɚммɚɯизɜлɟчɟнийɯолоɫɬоɝонɚɛлюɞɚлоɫьпикоɜɭɞɟɪжиɜɚнияɫооɬɜɟɬɫɬɜɭющимɭɞɟɪжиɜɚнияКОНчɬоɫɜиɞɟɬɟльɫɬɜɭɟɬɫɟлɟкɬиɜноɫɬимɟɬоɞикиоцɟнкɟлинɟйноɫɬимɟɬоɞикипɪиɝоɬоɜлɟныпɪоɚнɚлизиɪоɜɚны 8 моɞɟльныɯɪɚɫɬɜоɪоɜмочикɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜконцɟнɬɪɚциɟйКОНɞиɚпɚзонɟ 0,5 125 ɍɪɚɜнɟниɟкɚлиɛɪоɜочноɝоɝɪɚɮикɚ Y = 2189*X. эɮɮициɟнɬкоɪɪɟляцииɫоɫɬɚɜил 0,99865, чɬопоɞɌɚɛлицɚОɬклонɟнияконцɟнɬɪɚцийкɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜɮɚкɬичɟɫкиɯзнɚчɟнийɮɚкɬ0,692,097,7925,150,283,3100,4125,5ɪɚɫɫчиɬ0,632,157,8422,9748,2381,46100,86128,84,%-8,72,875,0-8,48-3,92-2,20,462,66Ноɪмɚɛолɟɟ20% ɛолɟɟɊиɫɭнокɏɪомɚɬоɝɪɚммɚизɜлɟчɟнияɯолоɫɬоймочиɊиɫɭнокɏɪомɚɬоɝɪɚммɚизɜлɟчɟниямоɞɟльнойɫмɟɫимочиконцɟнɬɪɚциɟйКОНɬɜɟɪжɞɚɟɬлинɟйноɫɬьмɟɬоɞикиɭкɚзɚнномɞиɚпɚзоКɚлиɛɪоɜочныйпɪɟɞɫɬɚɜлɟнɪиɫɭнкɟ 5. ɬɚɛлицɟ 1 пɪɟɞɫɬɚɜлɟныɪɟзɭльɬɚɬыоɛɪɚɬноɝопɟɪɟɪɚɫчɟɬɚконцɟнɬɪɚцийкɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜполɭчɟнныɯиɫпользоɜɚниɟмкɚлиɛɪоɜочноɝоɝɪɚɮикɚPharmacy & Pharmacology V. 5 N 4, 2017ɊиɫɭнокКɚлиɛɪоɜочныйколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏЭкɫпɟɪимɟнɬɚльноɪɚɫɫчиɬɚнныɟконцɟнɬɪɚциикɚлиɛɪоɜочныɯɫɬɚнɞɚɪɬоɜпɪɟɜышɚюɬпɪɟɞɟлоɜноминɚльныɯчɬоɫооɬɜɟɬɫɬɜɭɟɬпɪиɟмлɟмоɫɬи6 моɞɟльныɯконɬɪолякɚчɟɫɬɜɚ 5 концɟнɬɪɚцийКОН 111,56 пɪиɝоɬоɜпоɞɬɜɟɪжɞɟнияпɪиɝоɞноɫɬимɟɬоɞикипɚɪɚмɟɬɪɚмпɪɟцизионноɫɬьпɪɚɜильноɫɬьПоɞɝоɬоɜкɭɚнɚлизɚоɫɭщɟɫɬɜлялиɫооɬɜɟɬɫɬɜииопиɫɚнноймɟɬоɞикойПɪɟцизионноɫɬьпɪɚɜильноɫɬьмɟɬоɞикиоцɟниɜɚлиɜɟличинɚмоɬноɫиɬɟльноɝоɫɬɚнɞɚɪɬноɝооɬклонɟния (RSD, %) оɬноɫиɬɟльнойпоɝɪɟшноɫɬиɫооɬɜɟɬɫɬɜɟнноМɟɬɪолоɝичɟɫкиɟɯɚɪɚкɬɟɪиɫɬикимɟɬоɞикипɪɟɞɫɬɚɜлɟныɬɚɛлицɟɌɚɛлицɚМɟɬɪолоɝичɟɫкиɟɯɚɪɚкɬɟɪиɫɬикиколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟмɟɬоɞомȼЭЖɏКонцɟнɬɪɚцияКОНмоɞɟльнойɫмɟɫиконцɟнɬɪɚцияSDRSD, %0,560,64; 0,58; 0,66; 0,53; 0,600,04677,78177,143,363,12; 3,41; 3,90; 3,75; 3,570,33529,38576,2516,8016,87; 16,95; 17,42; 17,310,37232,15123,0462,7555,51; 57,65; 58,47; 57,761,43752,4890-7,95111,5698,57; 101,98; 102,53; 102,763,70753,6079-7,89Полɭчɟнныɟɪɟзɭльɬɚɬыконɬɪоляпɪɟɜышɚюɬɞопɭɫкɚɟмыɯɛиоɚнɚлиɬичɟɫкиɯмɟɬоɞикчɬоɫɜиɞɟɬɟльɫɬɜɭɟɬоɬɫɭɬɫɬɜиизнɚчимыɯмɚɬичɟɫкиɯɪɟзɭльɬɚɬɚɯɚнɚлизɚ [19, 20, ɎɚɪмɚкокинɟɬичɟɫкиɟиɫɫлɟɞоɜɚнияɬɚннɚямɟɬоɞикɚиɫпользоɜɚнɚпɪоɜɟɞɟнииɞоклиничɟɫкиɯɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнийэкɫкɪɟцииКОНлɚɛоɪɚɬоɪныɯжиɜоɬныɯЭкɫжиɜоɬныɯоɫɭщɟɫɬɜлялɫяɫооɬɜɟɬɫɬɜииɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistryпɪɚɜоɜыминоɪмɚмииɫпользоɜɚнияжиɜоɬныɯпɪоɜɟɞɟнииɞоклиничɟɫкиɯиɫɫлɟɞоɜɚнийoxicological ChemistryОпыɬ пɪоɜоɞилиɛɟлыɯɫɚɯɫɚмцɚɯмɚɫɫойполɭчɟнныɯɜиɜɚɪияПɟɪмɫкойɮɚɪмɚцɟɜɬичɟɫкойɚкɚɞɟмииЖиɜоɬныɟɫоɞɟɪжɚлиɫьɫɬɚционɚɪныɯɟɫɬɟɫɬɜɟнномɫɜɟɬоɜомɫɬɚнɞɚɪɬном 20 нɚчɚлɚэкɫпɟɪимɟнɬɚжиɜоɬныɯлишɚлиɋɭɛɫɬɚнциюКОНɜɜоɞилиоɞнокɪɚɬноɪɚльноɫɭɫпɟнзиикɪɚɯмɚльной 100 ɋɛоɪэкɫкɪɟɬоɜоɫɭщɟɫɬɜлялимɟɬɚɛоличɟɫкиɯклɟɬкɚɯɬɟчɟниɟ 24 поɫлɟɜɜɟɞɟнияКОНɊɟзɭльɬɚɬыколичɟɫɬɜɟнноɝоɚнɚлизɚКОНмочипɪɟɞɫɬɚɜлɟныɬɚɛлицɟɌɚɛлицɚɋɭɬочноɟɫоɞɟɪжɚниɟКОНмочɟоɞнокɪɚɬноɝоɜɜɟɞɟнияɞозɟМɚɫɫɚОɛъɟммочиɪɭжɟннɚяконцɟнɬɪɚцияɜɜɟɞɟнной320,01794,755,0400,01960,232,9370,02183,584,9340,014141,835,9350,01787,084,2340,02467,874,7 = 4,6%ɌɚкимиоɛɪɚзомпɪоɜɟɞɟнныɟиɫɫлɟɞоɜɚниякɚзɚличɬопоɫлɟоɞнокɪɚɬноɝопɟɪоɪɚльноɝоɜɜɟкɪыɫɚмɫɭɛɫɬɚнцииКОН 100 мочойɫɭɬкиɫɪɟɞнɟмɜыɜоɞиɬɫяоколо 5 % ɜɟщɟɫɬɜɚнɟизмɟнномЗɚключɟниɟɊɚзɪɚɛоɬɚнɚмɟɬоɞикɚколичɟɫɬɜɟнноɝоопɪɟɞɟлɟнияКОНмочɟɜключɚющɚяɫɟɛяжиɞкоɫɬьжиɞкоɫɬнɭюэкɫɬɪɚкциюɚнɚлиɬɚпоɫлɟɞɭющимɟɝоопɪɟɞɟлɟниɟммɟɬоɞомȼЭЖɏɜɚлиɞɚционнойɭɫɬɚноɜлɟнɚлɟкɬиɜноɫɬьлинɟйноɫɬьпɪɚɜильноɫɬьонноɫɬьмɟɬоɞикиМɟɬоɞикɚиɫпользоɜɚнɚɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚнияɯизɭчɟнииэкɫкɪɟцииКОНмочойлɚɛоɪɚɬоɪныɯжиɜоɬПокɚзɚночɬопоɫлɟоɞнокɪɚɬноɝопɟɪоɪɚльноɝоɜɜɟɞɟниякɪыɫɚмɫɭɛɫɬɚнцииКОН 100 мочойɫɭɬкиɫɪɟɞнɟмɜыɜоɞиɬɫяоколо 5% ɜɟщɟɫɬɜɚнɟизмɟнномIntroduction.decrease in memory, attention and mental performance. Cognitive disorders adversely affect the quality of life of the patient and need correction [1]. The drugs of choice in the complex therapy in this case are nootropics. Cur-rently, they are the only group of pharmacological agents with a pronounced neurometabolic effect. On the world have a wide spectrum of pharmacological activity.Cur-rently, this group continues to expand. By the employees of Perm State Pharmaceutical Academy (PSPA), ruled by Professor V.L. Gein, a new biologically active compound .L. Gein, a new biologically active compound ()synthesized.This compound is at the preclinical research stage now. Pharmacy & Pharmacology V. 5 N 4, 2017tice is feasible only when studying a detailed assessment c pharmacological activity and safety at the stage of experimental (preclinical) studies. The purpose of ior of potential drugs in the body of laboratory animals, i.e. the processes of absorption, distribution, metabolism and excretion [3]. The study of excretion is an important stage of the preclinical, which allows estimating the rate of elimination of potential drugs. In this connection, studies termination of biologically active compounds in biological uids, particularly in urine, are relevant. performance liquid chromatography with ? uorimetric [5] and mass selective detection [6-12] are used. The drug substance. Thus, for pharmacokinetic studies of Thus, for pharmacokinetic studies of of the sample with water [16]. The previous studies have shown that KOH-1 is effectively extracted from urine at fectively extracted from urine at The aim of this work was working out methods for determination of KOH-1 in urine by high performance liquid chromatography (HPLC), the study of excretion of KOH-1 from the organism of laboratory animalsin PSPA and corresponding to the requirements of the and corresponding to the requirements of the also the following reagents: acetonitrile (HPLC grade, Merckdrogen phosphate (cp), chloroform (cp). The water for UV water puri cation system (Millipore, Merck).LC-20 Prominence (Shi-madzu, Japan) with a diode-array detector,graphic column Luna 5uC18 (2) 100A (250 ? 4.6 mm, Phenomenex). A mixture of acetonitrile and phosphate buffer (pH 7) was used as the mobile phase. The detec-traction with chloroform. To do this, 1 ml of a model ed with l). Then double extraction with tube vortex. The time of each extraction was 1 minute. at 5000 rpm for 5 minutes. The organic layer was trans-solved in 1 ml of methanol. The extracts were ltered lters with a pore size lters with a pore size The validation of the developed method was carried out in accordance with modern requirements for bioan-alytical methods, in terms of selectivity, linearity, preci-, preci-The study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g, ob-tained from the vivarium of PSPA. The substance KOH-1 Chromatography and de-The previous studies have shown the effectiveness of using the eluent on the basis of ace-tonitrile and phosphate buffer (pH 7) for the analysis of 3-hydroxy-3-pyrrolin-2-one derivatives [22]. In this mobile phase, the maximum absorption of KOH-1 is 324 nm (Fig. 2), which ensures high selectivity of its jects. It was found out that the retention time of the test substance strongly depends on the concentration of phosphate buffer (pH 7) in the composition of the eluent. Increasing the buffer solution in the eluent from 6% to 11 minutes. A mixture of phosphate buffer (pH 7) and ow of 1 ml / min pro-vided an acceptable KOH-1 retention factor, good sep-it was used as the mobile phase. The retention time of Validation of the developed urine by the HPLC-UV method was carried out in terms of selectivity, linearity, precision and accuracy in accor--The selectivity of the method was established by an-alyzing the extracts from ?blank? urine samples, as well as model urine mixtures with KOH-1 concentration of 20 μg / ml. The chromatograms of the extracts from the blank sample showed no peaks with retention time cor-prepared and analyzed. The equation of the calibration graph had the form Y = 2189 * X. The correlation coef- cient was 0.99865, which con rms the linearity of the technique in this range. The calibration graph is shown Table 1 shows the results of the reverse recalculation ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological ChemistryFigure 2 ? UV spectrum of KOH-1 in the mobile phasePharmacy & Pharmacology V. 5 N 4, 2017Table 1 0.692.097.7925.150.283.3100.4125.50.632.157.8422.9748.2381.46100.86128.84,%-8.72.875.0-8.48-3.92-2.20.462.6620, 21].6 model bio-samples (quality control samples) at 5 concentration levels of KOH-1 (0.56; 3.36; 16.80; 62.75 and 111.56 rm the suitabil-ity of the technique in terms of precision and accuracy. , %), respectively. Metrological characteristics of the method are presented in Table 2.Table 2 ? Metrological characteristics of the quantitative determination of KOH-1 in urine by HPLCKOH-1 in the model mixture, g / mlFound concentration, g / mlSDRSD, %0.560.64; 0.58; 0.66; 0.600.04677.78177.143.363.12; 3.41; 3.90; 3.570.33529.38576.2516.8016.87; 16.95; 17.42; 17.310.37232.15123.0462.7555.51; 57.65; 58.47; 57.761.43752.4890-7.95111.5698.57; 101.98; 102.763.70753.6079-7.89ɎɚɪмɚцияɮɚɪмɚколоɝияɎɚɪмɚцɟɜɬичɟɫкɚяɬокɫиколоɝичɟɫкɚяPharmaceutical and Toxicological Chemistry cant systematic errors in the results of cant systematic errors in the results of Pharmacokinetic studies. The developed technique was used for preclinical pharmacokinetic studies on KOH-1 excretion in laboratory animals. An animal ex-An animal ex-Study of excretion of KOH-1 was performed on white non-linear male rats weighing 300-400 g, obtained from the vivarium of PSPA. The animals were kept in stationary conditions in natural light mode on a standard diet. 20 hours before the experiment the animals were deprived of food. The sub-stance KOH-1 was administered once orally in suspension creta was performed in metabolic cages for 24 hours after administration of KOH-1. The results of quantitative anal-ysis of KOH-1 in urine samples are presented in Table 3.Table 3 ? Daily content of KOH-1 in the urine of rats after a single oral administration Rat weight, gVolume of urine, ml320.01794.755.0400.01960.232.9370.02183.584.9340.014141.835.9350.01787.084.2340.02467.874.7 = 4.6 %gle oral administration of KOH-1 to the rats in the dose of 100 mg/kg, about 5% of the substance on changed form. subsequent determination by HPLC / UV.The selectivity, linearity, accuracy and precision of the methodology were established by the validation The technique has been successfully used cretion in urine in laboratory animals. It is shown that after a single oral administration of KOH-1 to the rats in the dose of 100 mg/kg, about 5% of the substance changed form. ȻиɛлиоɝɪɚɮичɟɫкийɍшкɚлоɜɚɍшкɚлоɜɚɎȺɊМȺКОɌȿɊȺПИЯКОȽНИɌИȼНЫɏНȺɊɍШȿНИЙɊȺЗЛИЧНОȽОȽȿНȿЗȺɋОɋɌОЯНИȿПȿɊɋПȿКɌИȼНЫȿНȺПɊȺȼЛȿНИЯ //ɊМЖ 22. КоллɚȺНɌИȺМНȿɋɌИЧȿɋКОȿПɊОИЗȼОȾНЫɏɊЯȾȺ 3-ȽИȾɊОКПИɊɊОЛИНЭкɫпɟɪимɟнɬɚльнɚяклиничɟɫкɚяɮɚɪмɚколоɝияМɟньшикоɜɚПɟчɟнкинɚȻɟɪɟзɚОɋОȻȿННОɋɌИИɋɋЛȿȾОȼȺИННОȼȺЦИОННЫɏЛȿКȺɊɋɌȼȿННЫɏПɊȿПȺɊȺɌОȼКОɊОɌКОȿНɚɭчпɪоизɜоɞɫɬɜжɭɪнɚлɊɚзɪɚɛоɬкɚɪɟɝиɫɬɪɚцияɞɚɬɚ.) ȺнɬоноɜɚПɪокопоɜȺɯɚпкинɚȻɟɪлянɞКОЛИЧȿɋɌȼȿННЫЙɎȿНОɌɊОȻИОЛОȽИЧȿɋКИɏОȻЪȿКɌȺɏМȿɌОȾОМȽȺЗОЖИȾКОɋɌНОЙɏɊОМȺɌОȽɊȺɎИИ // ɮɚɪмжɭɪнSimpson R.C., Boppana V.K., Hwang B.Y., Rhodes G.R. DETERMINATION OF OXIRACETAM IN HUMAN PLASMA BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH Journal of Chromatography. 1993. No. 631 (1-2). P. 227?232. Zhang J., Liang J., Tian Y., Zhang Z., Chen Y. 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COMPARATIVE PHARMACOKINETIC STUDIES OF RACEMIC OXIRACETAM AND ITS PURE ENANTIOMERS AFTER ORAL ADMINISTRATION IN RATS BY A STEREOSELECTIVE HPLC METHOD // . 2015. No. 111. P. 153-158. DOI: 10.1016/j.jpba.2015.03.039Son J., Lee J., Lee M., Lee E., Lee K.T., La S., Kim D.H. RAPID QUANTITATIVE ANALYSIS OF OXIRACETAM IN HUMAN PLASMA BY LIQUID CHROMATOGRAPHY/ELECTROSPRAY TANDEM MASS SPECTROMETRY // . 2004. No. 36 (1). P. 183?187. Wan X., Wang H., Ma P., Xi L., Sun J., He Z., Zhang X., Liu X. SIMULTANEOUS DETERMINATION OF OXIRACETAM AND ITS DEGRADED SUBSTANCE IN RAT PLASMA BY HPLC-MS/MS AND ITS APPLICATION TO PHARMACOKINETIC STUDY AFTER A SINGLE HIGH-DOSE INTRAVENOUS ADMINISTRATION // Journal of chromatography B analytical technologies in the biomedical and life sciences.2014. No. 969. P. 95-100. DOI: 10.1016/j.jchromb.2014.07.041 Wang X., Zhu J., Xu R., Yang X., Wu H., Lin D., Ye F., Hu L. DETERMINATION OF PIRACETAM IN RAT PLASMA BY LC-MS/MS AND ITS APPLICATION TO PHARMACOKINETICS // Biomedical Chromatography. 2010. No. 24(10). P. 1108?1112. DOI: 10.1002/bmc.1412.ПɪокопоɜКоɬлоɜɚȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИɌȿɌɊȺМȿЗИНȺɮɚɪмжɭɪнПɪокопоɜКоɫɬɟɛɟлоɜȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИȺЛЬȻИКȺɊȺОɊȽȺНИЗМȺɮɚɪмжɭɪнȺнɬоноɜɚПɪокопоɜȺɯɚпкинɚȻɟɪлянɞИЗɍЧȿНИȿЭКɋКɊȿЦИИПɊȿПȺɊȺɌȺɎȿНОɌɊОПИЛОɊȽȺНИЗМȺ // ɮɚɪмжɭɪн 11. Farhan A.S., Nawab S., Nighat S., Alisha W.S., Ahmad M.,Mehjebeen, Naseem H. DEVELOPMENT OF NEW METHOD FOR SIMULTANEOUS ANALYSIS OF PIRACETAM AND LEVETIRACETAM IN PHARMACEUTICALS AND BIOLOGICAL FLUIDS: APPLICATION IN STABILITY STUDIES // Research International. 2014. Vol. 2014. Article ID 758283, 8 pages. DOI:10.1155/2014/758283ȻɭлɝɚкоɜɚКɚɪпɟнкоȼЫȻОɊɍɋЛОȼИЙИЗȼЛȿЧȿНИЯȻИОЛОȽИЧȿɋКИПɊОИЗȼОȾНЫɏ 3-ПИɊɊОЛИНМОЧИ // ИнноɜɚционнɚянɚɭкɚмɟжɞɭнɚɪоɞнɚɭчныйжɭɪнɚлɌомКляшɟɜɚ., ȽɟйнОɞɟɝоɜɚɋɚɬɬɚɪоɜɚКɚɪпɟнкоɊȺЗɊȺȻОɌКȺɌОȾОȼКȺЧȿɋɌȼȺɋɍȻɋɌȺНЦИИНОȼОȽОȻИОЛОȽИЧȿɋКИȺКɌИȼНОȽОКОНɎɚɪмɚцияand Drug Administration, Center for Drug Evolution and Research (CDER). U.S. Government Printing Of ce. Washington, DC, 2001. 25 p.Guideline on validation of bioanalytical methods (draft) / European Medicines Agency. Committee for medicinal Ɋɟшɟниɟɋоɜɟɬɚȿɜɪɚзийɫкойэкономичɟɫкойкомиɫɫии 03.11.2016 85 ?ɭɬɜɟɪжɞɟнииɜɟɞɟнияиɫɫлɟɞоɜɚнийɛиоэкɜиɜɚлɟнɬноɫɬилɟкɚɪɫɬɜɟнныɯпɪɟпɚɪɚɬоɜɪɚмкɚɯȿɜɪɚзийɫкоɝоэкономичɟɫкоɝоМɚнɬɭɪоɜКɚɪпɟнкоɊɚзɪɚɛоɬкɚопɪɟɞɟлɟнияɛиолоɝичɟɫкиɚкɬиɜноɝоɫоɟɞинɟниямɟɬоɞомȼЭЖɏɮɚɪмɚкокинɟɬичɟɫкиɯиɫɫлɟɞоɜɚний // ɊɚзɪɚɛоɬкɚиɫɫлɟɞоɜɚниɟмɚɪкɟɬинɝноɜойɮɚɪмɚцɟɜɬичɟɫкойпɪоɞɭкциинɚɭчПяɬиɝоɪɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияПяɬиɝоɪɫкɭɬɜɟɪжɞɟниилɚɛоɪɚɬоɪнойпɪɚкɬикипɪикɚзМиниɫɬɟɪɫɬɜɚзɞɪɚɜооɯɪɚнɟнияɫоциɚльноɝоɊоɫɫийɫкойɎɟɞɟɪɚции 23 ɚɜɝɭɫɬɚ 2010 . URL: http://www.consultant.ru/document/cons_doc_LAW_105953/ (ɞɚɬɚ: 11.01.2017 ReferencesUshkalova E.A., Ushkalova A.V. FARMAKOTERAPIJA KOGNITIVNYH NARUSHENIJ RAZLICHNOGO GENEZA: SOVREMENNOE SOSTOJANIE I PERSPEKTIVNYE NAPRAVLENIJA [PHARMACOTHERA-PY OF COGNITIVE DISTURBANCES OF VARIOUS GENESIS: MODERN STATE AND PERSPECTIVE AND PERSPECTIVE 2014. N 22. P.1613. (In Russ.)Shuklina N.S., Kolla V.Je. 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(in Russ.)of the Ministry of Health and Social Development of the Russian Federation of August 23, 2010 708-n]. URL: http://www.consultant.ru/document/cons_doc_LAW_105953/ (access data: 11.01.2017). (in Russ.) ict of interest ict of interest.Candidate of Sciences (Pharmacy), Associate Professor of the Department of Toxicological Chemistry, Perm State Pharmaceutical Academy. Research interests: development and valida-tion of bioanalytical techniques, research in the eld of pharmacokinetic studies, high-performance liquid chro-matography. E-mail: karpenko_pfa @ mail.ruYarygina Tatyana Ivanovna (Pharmacy), Professor of the Department of Pharmaceu-tical Chemistry, Faculty of Full-time Studies, Perm State Pharmaceutical Academy. Research interests: develop-ment of methods for quality control and standardization of biologically active compounds from gamma-aminobu-tyric acid and 3-hydroxy-3-pyrrolin-2-one groups; devel-opment of new and improvement of known spectrophoto-Bulgakova Evgenia Aleksandrovna the Department of Toxicological Chemistry, Perm State Pharmaceutical Academy. Research interests: develop-ment and validation of bioanalytical techniques, phar-macokinetic studies, high-performance liquid chroma-tography. E-mail: bugakova_pfa @ mail.ruКонɮликɬинɬɟɪɟɫоɜȺɜɬоɪызɚяɜляюɬоɬɫɭɬɫɬɜииконɮликɬɚинɬɟɪɟɫоɜȺɜɬоɪыКɚɪпɟнкоНиколɚɟɜнɚ ? кɚнɞиɞɚɬмɚцɟɜɬичɟɫкиɯнɚɭкɞоцɟнɬкɚɮɟɞɪы ɬокɫиколоɝичɟɫкой, ПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚɜɚлиɞɚцияɛиоɚнɚлиɬичɟɫкиɯмɟɬоɞикиɫɫлɟɞоɜɚнияоɛлɚɫɬиɮɚɪмɚцɟɜɬичɟɫкоɝоɬокɫиколоɝичɟɫкоɝоɮɚɪмɚкокинɟɬичɟиɫɫлɟɞоɜɚнияɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоɝɪɚɮия. E-mail: karpenko_pfa@ mail.ruɌɚɬьянɚИɜɚноɜнɚ ? ɞокɬоɪɮɚɪмɚцɟɜɬичɟɫкиɯнɚɭкпɪоɮɟɫɫоɪкɚɮɟɞɪыɮɚɪмɚцɟɜɬичɟɫкойɮɚкɭльɬɟɬɚочноɝооɛɭчɟнияПɟɪмɫкɚяɝоɫɭɞɚɪɫɬɜɟннɚяɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚмɟɬоɞоɜконɬɪолякɚчɟɫɬɜɚɫɬɚнɞɚɪɬизɚцииɛиолоɝичɟɫкиɚкɬиɜныɯɫоɟɞинɟнийɝɪɭпппɪоизɜоɞныɯминомɚɫлянойкиɫлоɬы 3-ɝиɞɪокɫипиɪɪолинɪɚзɪɚɛоɬкɚɫоɜɟɪшɟнɫɬɜоɜɚниɟизɜɟɫɬɫпɟкɬɪоɮоɬомɟɬɪичɟɫкиɯмɟɬоɞиклɟкɚɪɫɬɜɟнныɯɫɪɟɞɫɬɜȻɭлɝɚкоɜɚȺлɟкɫɚнɞɪоɜнɚ ? кɚɮɟɞɪыɬокɫиколоɝичɟɫкойПɟɪмɫкɚяɝоɫɭɮɚɪмɚцɟɜɬичɟɫкɚяɚкɚɞɟмияОɛлɚɫɬьнɚɭчныɯинɬɟɪɟɫоɜɪɚзɪɚɛоɬкɚɜɚлиɞɚциялиɬичɟɫкиɯмɟɬоɞикɮɚɪмɚкокинɟɬичɟɫкиɟиɫɫлɟɞоɜɚнияɜыɫокоэɮɮɟкɬиɜнɚяжиɞкоɫɬнɚяɯɪомɚɬоПоɫɬɭпилɚɪɟɞɚкциюПɪиняɬɚпɟчɚɬи
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About the authors

E. A. Bulgakova

Perm State Pharmaceutical Academy

Email: karpenko_pfa@mail.ru

Yu. N. Karpenko

Perm State Pharmaceutical Academy

Email: fake@neicon.ru

T. I. Yarygina

Perm State Pharmaceutical Academy

Email: bugakova_pfa@mail.ru

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