Comparative study of perindopril and perindopril metabolite pharmacokinetics using the HPLC/MS method

Perindopril is a prodrug which is converted to an active metabolite perindoprilat in the human organism. The present study led to the development of a fast and easily reproducible procedure for simultaneous detection of perinoprilat and its metabolite in plasma using HPLC with mass-spectrometric detector (LC-MS). Detection of the target substance was performed using atmospheric pressure electrospray ionization (API-ES) techniques in negative polarity in two modes: SIM1, ion, m/z=368,10 for perindopril and SIM2, ion, m/z=339,30 for perindoprilat. Retention time of perindopril was about 2,4 min, for perindoprilat - about 1,4 min. Sample processing was performed using solid-phase extraction. The method’s limit of quantification was equal to 1 ng/ml for perindopril and 1 ng/ml for perindoprilat. The developed procedure was used to analyse pharmacokinetics and bioequivalence of medicines containing 8 mg of perindopril. Values of all calculated pharmacokinetic parameters had no statistically meaningful differences. Confidence intervals obtained fall within bioequivalence criterion (80-125% for AUC and 75-133% for Сmax и Cmax/AUC). The medicines under analysis were found to be bioequivalent

Перспективы использования «коктейльных» методов определения активности изоферментов цитохрома P450 in vivo с целью рационализации фармакотерапии

Rational pharmacotherapy is understood as intelligent drug combination and dosage adjustment for the purpose of drug adverse events development risk minimization and achievement of suitable therapeutical effect. One of the main factors affecting on drug potency is activity of biotransformation system. In this work, a review of promising "cocktail" method of biotransformation enzymes activity determination in vivo is given.Под рациональной фармакотерапией подразумевается грамотное комбинирование лекарственных препаратов и корректировка их доз с целью минимизации риска развитий нежелательных лекарственных реакций и достижения необходимого терапевтического эффекта. Одним из важнейших факторов, влияющих на эффективность действия лекарственных средств, является активность системы метаболизма. В данной статье проведён обзор перспективного «коктейльного» метода определения активности ферментов биотрансформации in vivo

Comprehensive Screening for COVID-19 at St. Petersburg Oncology Centre

Background. Clinical reports on the coronavirus disease 2019 (COVID-19) suggest its higher incidence and worse outcomes in cancer patients. Considering a rapid pace of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic, more data on the risk of contagion and syndrome course is required with this patient group.Aim. Estimation of the infection rate in cancer patients managed at the Oncology Centre.Materials and methods. This retrospective study included cancer patients managed at the Oncology Centre between 9 April 2020 and 27 May 2020 and routinely tested for SARS-CoV-2 in polymerase chain reaction (PCR) assays and/or COVID-19 in chest computed tomography (CT).Results and discussion. A total of 2,628 patients were included in the study, with 119 (4.5 %) confirmed to have COVID-19; 45/119 were PCR-positive, 95/119 had viral pneumonia in CT, 21/119 were positive for both tests. A total of 47.9 % cases were asymptomatic, 11.8 % revealed a mild single-symptom disease. COVID-19 ended in death in 2 (2.5 %) of 80 cases with a known outcome. In PCR results of both patient and staff screening, the virus detection rate was 3.0 % and 2.4 %, respectively (p = 0.33).Conclusion. A COVID-19 screening revealed no significant difference in the risk of contagion between cancer patients and staff of the Oncology Centre. PCR tests may perform false negative for COVID-19 in cancer patients and should be coupled with CT scanning. The infection is asymptomatic or clinically mild in most other cases

Влияние изофермента CYP2D6 на метаболизм лекарственных препаратов и методы определения его активности

The article presents relevant information on the features of cytochrome P450 isoenzyme CYP2D6 functioning. 20-25% of drugs are metabolized by the action of CYP2D6. Determination of its activity allows for adjusting pharmacotherapy to increase the efficacy and safety of a drug or a combination of drugs. Cytochrome P450 isoenzymes genotyping and phenotyping methods allow for choosing the dosage and dosing regimen for patients on an individual basis. This article describes the genetic characteristics affecting CYP2D6. CYP2D6 polymorphism has a significant impact on pharmacokinetics and metabolism of a drug. This may lead to side effects, or decrease the pharmacological action of the drug. The article covers the cases of change in clinical response to receiving β-blockers (metoprolol), antidepressants (venlafaxine) and opioids (codeine). These changes occurred in the presence of certain CYP2D6 alleles which speed up or slow down the metabolism. It also provides information on drug-drug interactions involving inhibition of cytochrome P450 isoenzyme CYP2D6. Genotyping methods are used to determine the potential activity of CYP2D6. Dose adjustment is carried out basing on the results obtained. The current isoenzyme status is defined by phenotyping methods. CYP2D6 activity can be evaluated by determining the ratio of the substrate and its metabolite using HPLC. Pinoline, which is metabolized to 6-hydroxy-1,2,3,4-tetrahydro-β-carboline, is the endogenous substrate for estimating the activity of CYP2D6.В статье приведена актуальная информация об особенностях функционирования изофермента цитохрома Р450 CYP2D6. Метаболизм 20-25% лекарственных препаратов происходит под действием изофермента CYP2D6. Определение его активности позволяет скорректировать фармакотерапию с увеличением эффективности и безопасности препарата или комбинации препаратов. Методы генотипирования и фенотипирования изоферментов цитохрома Р450 позволяют индивидуально для пациента подбирать дозировку, режим дозирования. В статье описаны генетические особенности, которые оказывают воздействие на изофермент CYP2D6. Полиморфизм изофермента CYP2D6 оказывает существенное влияние на метаболизм и фармакокинетику лекарственного препарата, что может привести кпобочным эффектом или снижению фармакологического действия препарата. Рассмотрены случаи изменения клинического ответа на прием β-блокаторов (метопролол), антидепрессантов (венфлаксин) и опиоидов (кодеин). Данные изменения происходили при наличии определенных аллелей CYP2D6, которые ускоряют или замедляют метаболизм. Также представлена информация о межлекарственном взаимодействиях, при которых происходит ингибирование изофермента цитохрома Р450 CYP2D6. Для определения потенциальной активности изофермента CYP2D6 используются методы генотипирования. На основании полученных результатов, проводится корректировка дозы. Текущий статус изофермента определяется методами фенотипирования. Определение соотношения субстрата и его метаболита методом высокоэффективной жидкостной хроматографии позволяют произвести оценку активности изофермента. Эндогенным субстратом для определения активности изофермента CYP2D6 является пинолин, метаболитом которого является 6-гидрокси-1,2,3,4-тетрагидро-β-карболин

Сравнительное изучение фармакокинетики периндоприла и его метаболита с помощью разработанного метода ВЭЖХ/МС

Perindopril is a prodrug which is converted to an active metabolite perindoprilat in the human organism. The present study led to the development of a fast and easily reproducible procedure for simultaneous detection of perinoprilat and its metabolite in plasma using HPLC with mass-spectrometric detector (LC-MS). Detection of the target substance was performed using atmospheric pressure electrospray ionization (API-ES) techniques in negative polarity in two modes: SIM1, ion, m/z=368,10 for perindopril and SIM2, ion, m/z=339,30 for perindoprilat. Retention time of perindopril was about 2,4 min, for perindoprilat - about 1,4 min. Sample processing was performed using solid-phase extraction. The method’s limit of quantification was equal to 1 ng/ml for perindopril and 1 ng/ml for perindoprilat. The developed procedure was used to analyse pharmacokinetics and bioequivalence of medicines containing 8 mg of perindopril. Values of all calculated pharmacokinetic parameters had no statistically meaningful differences. Confidence intervals obtained fall within bioequivalence criterion (80-125% for AUC and 75-133% for Сmax и Cmax/AUC). The medicines under analysis were found to be bioequivalent.Периндоприл является пролекарством, из которого в организме образуется более активный метаболит перин-доприлат. В результате проведенного исследования разработана быстрая и легко воспроизводимая методика совместного определения периндоприлата и его метаболита в плазме крови с применением ВЭЖХ с масс-спектрометрическим детектором (LC-MS). Детектирование целевого соединения проводили в режиме ионизации при атмосферном давлении в электроспрее (API-ES) в негативной полярности в двух режимах: SIM1 по иону m/z=368,10 для периндоприла и SIM2 по иону m/ z=339,30 для пенидоприлата. Время удерживания периндоприла составило около 2,4 мин, для периндоприлата - около 1,4 мин. В качестве пробоподготовки использовался метод твердофазной экстракции. Предел количественного определения методики составил 1 нг/мл для периндоприла и 1 нг/мл для периндоприлата. Разработанный метод был применен для изучения фармакокинетики и биоэквивалентности препаратов, содержащих периндоприл в дозе 8 мг. Значения всех рассчитанных параметров фармакокинетики статистически достоверно не отличались. Полученные доверительные интервалы попадают в интервал критерия биоэквивалентности (80-125% для AUC и 75-133% для Сmax и Cmax/AUC). Изучаемые препараты биоэквивалентны

Possible benefits of evaluation the coefficient of variation of active substance of a drug from different manufactures based on benzydamine hydrochloride example

Acute respiratory viral infection (ARVI) is one of the most common causes of morbidity in Russia. The incidence rate is high regardless of age or social group [1]. Sore throat is the most common symptom during ARVI, prevalence rate is 95%[2]. Symptomatic treatment of ARVI requires the use of various drugs, including drugs for pain in the throat. Such preparations are widely represented on the market, while they have a different form and different composition. One of the most popular are sprays containing benzydamine hydrochloride. Professional associations recommend using Benzydamine hydrochloridewhile sore throat, also in paediatric practice [3].In connection with a large number of generics, the issue of standardization of such sprays is topical. To compare the range of the actual concentration of the active substance in interchangeable preparations with different trade names, a comparative determination of the concentrations of benzydamine hydrochloride in sprays of 4 trade names was carried out in 6 different series in each. The quantitative determination was carried out by HPLC with a UV detector. As a result, the active substance concentration ranges were determined in 6 batches of the preparation of each trade name, and the coefficient of variation of concentrations was calculated and conclusions were made on the difference in the indicated indices among preparations of various manufacturers

DEVELOPMENT AND VALIDATION OF SIMULTANEOUS ASSAY OF SUBSTRATES-MARKERS OF MAIN CYTOCHROME P450 ISOFORMS AND THEIR METABOLITES USING HPLC-MS/MS

Simultaneous quantification method of assaying main CYP isoforms substrates-markers and their metabolites in urine using HPLC-MS/MS was developed to determine activity of following isoforms: caffeine/paraxanthine for CYP1A2, losartane/E-3174 for CYP2C9, cortisole/6-β-hydroxycortisole for CYP3A4 and pinoline/6-hydroxy-1,2,3,4-tetrahydro-β-carboline for CYP2D6. Carbamazepine was used as internal standart. Urine was used as biological object, samples were prepared by extraction with ethyl acetate : hexane : diethyl ether (50:35:15) mixture continued with pH correction of urine sample using borate buffer (pH=9,4) and following extraction with ethyl acetate : hexane mixture (50:50). Method was successfully validated and can be put in clinical practice for CYP isoforms activity determination

«COCKTAIL» METHODS OF CYTOCHROME P450 ISOFORMS ACTIVITY DETERMINATION <i>IN VIVO</i> USING BIOANALYTICAL METHODS: ACTUAL METHODS REVIEW AND OPPORTUNITIES OF THEIR APPLICATION IN CLINICAL PRACTICE

The review of current «cocktail» phenotyping methods for biotransformation activity determination enabling simultaneous characterization of main cytochrome P450 isoforms activity was made. Furthermore, the possibility of their application in clinical practice in order to correct administered drugs dosage for the purpose of minimizing drug adverse reactions appearance risk was assessed

Biotechnological preparations as a means of improving the safety of pharmacotherapy: state of the art and prospects of development

Development and improvement of biotechnological drugs currently more relevant than ever. Drugs obtained by means of biotechnology, have a number of positive qualities. Biotechnology allows you to create such products, which are currently impossible to synthesize by chemical means, in addition, the production of drugs using biotechnology meets the standards of quality, efficacy and safety and, more importantly, economically. Biotech drugs are used for treatment of infectious, autoimmune, cancer, are used to prevent, thereby finding wide application in medicine