Methodical approaches to bioassay of substances containing unstable functional groups

This article describes the method development approaches for bioassay of substances containing unstable functional groups and forming unstable metabolites using the example of mycophenolic acid, methyldopa and mebeverine metabolite

Исследование сравнительной фармакокинетики таблетированных форм микофеноловой кислоты

In a single-dose, two-treatment, two-period, two-sequence crossover study with a 14-days washout period was carried out the bioequivalence study of two tablet coated formulation of mycophenolic acid that given to 48 volunteers in equal doses (dosage 360 mg). There were calculated the followed parameters: AUC0-t, Cmax, Tmax, Cmax/AUC. 90% confidence interval for ratio of geometric mean AUC0-t values was 98,97% - 111,49% and one for ratio of geometric mean Cmax was 121,27% - 153,94%. The upper limit of the confidence interval of Cmax valuesa goes beyond the permissible range according to the protocol study (75-133%). It is not possible to state bioequivalence of drugs. Possible causes of discrepancies of pharmacokinetic parameters were analyzed.В рамках открытого, рандомизированного, перекрёстного исследования с 14-дневным периодом отмывки, с двумя последовательностями была изучена биоэквивалентность двух таблетированных форм микофеноловой кислоты на 48 добровольцах (дозировка 360 мг). Для анализируемых препаратов рассчитаны следующие фармакокинетические параметры: AUC0-t, Cmax, Tmax, Cmax/AUC. 90% доверительные интервалы для отношения геометрических средних значений параметров AUC0-t и Cmax микофеноловой кислоты составили 98,97-111,49% и 121,27-153,94% соответственно. Верхняя граница доверительного интервала, соответствующего параметру Cmax, выходит за рамки допустимого согласно протоколу исследования диапазона (75-133%), что не позволило констатировать биоэквивалентность исследуемых препаратов. Также были проанализированы возможные причины расхождений фармакокинетических параметров

Исследование фармакокинетики мебеверина в форме капсул с пролонгированным высвобождением

Pharmacokinetic study of prolonged release capsules of mebeverine was carried out on 24 volunteers. It is known that the drug substance is completely metabolized due to first-pass effect. Therefore, pharmacokinetic parameters of the main metabolites -mebeverine acid and desmethyl mebeverine acid were measured. Bioanalytical method was developed to measurement of concentrations of these metabolites in blood plasma by using HPLC-MS/MS.Было проведено исследование фармакокинетики мебеверина в форме капсул с пролонгированным высвобождением на 24 здоровых добровольцах. Известно, что данное лекарственное вещество полностью метаболизируется на пресистемном этапе. Поэтому измерялись фармакокинетические параметры только его основных метаболитов - мебевериновой кислоты и деметилированной мебевериновой кислоты. Для определения концентрации данных метаболитов в плазме крови разработана биоаналитическая методика с использованием высокоэффективной жидкостной хроматографии с масс-спектрометрическим детектированием

Methodical approaches to bioassay of substances containing unstable functional groups

This article describes the method development approaches for bioassay of substances containing unstable functional groups and forming unstable metabolites using the example of mycophenolic acid, methyldopa and mebeverine metabolite

Confocal raman microspectroscopy and imaging study of theraphthal in living cancer cells.

Binary systems combining a transition metal complex and ascorbate have been proposed recently for catalytic therapy of malignant tumors. The killing effect on tumor cells is achieved by production of free radicals in the course of accelerated oxidation of ascorbate by dioxygen in the presence of transition metal complexes. Further progress in the development of binary catalytic systems (BCSs) requires a special method for their investigation in cells and tissues, because neither component of BCSs fluoresces. Here a resonance Raman confocal spectral imaging (RR CSI) technique was introduced as a unique approach to monitor quantitatively the transition metal complexes within living cells. Intracellular accumulation, localization, and retention of theraphthal (TP), a catalyst of the advanced TP/ascorbate BCS, were investigated in A549 cells with the RR CSI technique. The cellular analysis was complemented with the detailed study of molecular interactions of TP in solution and environmental factors affecting the RR spectrum of TP. TP does not penetrate into membranes, it binds very weakly to DNA and RNA, but it readily forms complexes with proteins. Binding with Ca(2+) cations and decreasing pH below 6 induce aggregation of TP. By analyzing RR spectra recorded from every point within a TP-treated cell, three states of the agent were discriminated, namely, monomeric TP in polar environment, TP bound to proteins, and aggregated TP. Their cytoplasmic and nuclear distributions were mapped at different stages of uptake and efflux. By introducing organelle-selective fluorescent probes into drug-treated cells and measuring intracellular localization of both the probe and the drug, compartmentation of TP was revealed. Cell growth suppression by the TP/ascorbate system was measured, and probable molecular and organelle targets of radical damage were characterized

Pharmacokinetic and Bioequivalence Study of Telzap AM^® (Telmisartan/amlodipine Fixed-dose Combination) and Coadministered Mikardis^® (Telmisartan) and Norvask^® (Amlodipine) in Healthy Subjects

Introduction. A fixed dose combination of telmisartan and amlodipine is widely used in clinical practice during hypertension treatment. Combination of telmisartan and amlodipine demonstrates potentiating synergistic effect on blood pressure decrease. A bioequivalence study of Telzap® AM with coadministered Mikardis® and Norvask® was conducted with 60 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® AM (telmisartan + amlodipine, tablets, 80 + 10 mg, Zentiva ks company, Czech Republic) and coadministrated monocomponent drug products Mikardis® (telmisartan, tablets 80 mg, Beringer Ingelheim International GmbH, Germany) and Norvask® [amlodipine, tablets 10 mg, Pfizer HCP Corporation (USA), Russia] in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate clinical trial was conducted. The concentrations of amlodipine and telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of amlodipine and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of amlodipine were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 76.73–130.32 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent