Comparison of Pharmacokinetics and Bioavailability of Fixed-Dose Combination Tablet and Monotherapy Combination of Allisartan Isoproxil and Indapamide Sustained-Release in Healthy Chinese Volunteers.

This study aimed to compare the pharmacokinetics and bioavailability of 2 formulations: a fixed-dose combination tablet containing allisartan isoproxil (AI) and indapamide sustained-release (SR), and a monotherapy combination of AI and indapamide SR, in healthy Chinese subjects. A monocentric, open-label, single-dose, randomized, 2-way crossover study design was implemented. A total of 38 healthy male and female volunteers were equally divided into 2 treatment sequences. The analysis of plasma concentrations was conducted using a nonstereospecific liquid chromatography/tandem mass spectrometric method. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. For the fixed-dose combination and monotherapy combination, the mean values of EXP3174 (metabolite of AI) Cmax , AUC0-t , and AUC0-∞ were 987 and 999 ng/mL, 8059 and 7749 ng/mL h, and 8332 and 8007 ng/mL h, respectively. The corresponding values for indapamide were 27 and 32 ng/mL, 1002 and 1105 ng/mL h, and 1080 and 1172 ng/mL h. No serious adverse events were reported during the study. The combination tablet containing 240 mg of AI and 1.5 mg of indapamide SR met the bioequivalence standards. Additionally, both formulations were tolerated and had good safety profiles in the research.

Pharmacokinetics and Drug-Drug Interaction of Allisartan Isoproxil and Indapamide Sustained-Release Formulation.

Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug-drug interactions of AI and an indapamide sustained-release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7-day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI + Ind SR) during 3 different cycles. Twenty-four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmax and the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration-time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations.

The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport-time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 µg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.

Simultaneous determination of indapamide, perindopril and its active metabolite perindoprilat in human plasma using UPLC-MS/MS method.

Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C18 (2.1 mm × 150 mm, 3.5 µm) with isocratic elution. The ion transitions at m/z 369.165 â†’ 172.000 (perindopril), m/z 341.146 â†’ 170.112 (perindoprilat), m/z 366.010 â†’ 132.100 (indapamide), m/z 389.120 â†’ 206.200 (S10211-1, IS1) and m/z 394.080 â†’ 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma.

Determination of amlodipine, indapamide and perindopril in human plasma by a novel LC-MS/MS method: Application to a bioequivalence study.

A robust and rapid UPLC-MS/MS method has been developed, optimized and validated for determination of amlodipine (AML), indapamide (IND) and perindopril (PRN) in human plasma. A positive electrospray ionization mode was used in a Xevo TQD LC-MS/MS instrument. A single sample preparation step using extraction technique was applied to extract the three analytes from plasma samples. There was no need to extract indapamide from blood samples in a further step. Extraction of the three drugs and internal standards was done using a solvent mixture composed of methyl tertiary butyl ether, dichloromethane and ethyl acetate. The prepared samples were analyzed using an Acquity UPLC HSS C18 (100 × 2.1 mm, 1.7 µm) column. Ammonium acetate and methanol, pumped at a flow rate of 0.3 ml/min, were used as a mobile phase. Method validation was done as per the US Food and Drug Administration guidelines. Linearity was achieved in the range of 0.2-15 ng/ml for AML, 0.5-50 ng/ml for IND and 0.5-120 ng/ml for PRN. Accuracy and precision were estimated and found to be within the acceptable ranges. The rapid chromatography permits analysis of many samples per batch, making the method suitable for clinical and pharmacokinetic investigations. The developed and validated method was applied to estimate AML, IND, and PRN in a fasting bioequivalence study in healthy human volunteers.

Insights into Dissolution and Solution Chemistry of Multidrug Formulations of Antihypertensive Drugs.

Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.

Combination Antihypertensive Therapy with Perindopril and Indapamide in Patients with Essential Hypertension: Effect on Endothelial and Cognitive Markers of Vascular Improvement.

INTRODUCTION: The objective of this study was to assess the impact of a single-pill combination (SPC) of perindopril/indapamide (PER/IND) at full doses (10/2.5 mg) on endothelial and cognitive function as a clinical intermediate marker of vascular improvement. METHODS: This open-label, uncontrolled, observational study enrolled 30 patients (20 females and 10 males) with grade II-III uncontrolled arterial hypertension (SBP/DBP ≥ 160/100 mmHg) and no evidence of cerebrovascular disease. All patients underwent assessment of macro- and microvascular endothelial function parameters at baseline and after 12 months of treatment with SPC PER/IND using photoplethysmography and video capillaroscopy. Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA). RESULTS: All patients (mean age 60.06 ± 10.19 years) were at high risk for cardiovascular events: mean body mass index (BMI) 31.2 ± 3.9 kg/m2, 33% diagnosed with coronary artery disease angina class I, 30% with impaired glucose tolerance, and 7% with type 2 diabetes. Impaired endothelial function was observed at the both micro- and macrovascular levels. Endothelial function parameters improved after 12-month treatment with SPC PER/IND with an increase in occlusion index from 1.4 to 1.8 (P < 0.00005) and phase shift from 5.0 to 10.8 (P < 0.00001); all values achieved levels in the normal range. Resting capillary network density (CND) increased from 44.8 to 52 cap/mm2 (P < 0.00007), and CND after a venous occlusion test increased from 55 to 61 cap/mm2 (P < 0.006). Signs of cognitive impairment were present at baseline with a mean MoCA score of 23 (normal cognitive function score ≥ 26), but improved after 12-month treatment with a mean MoCA score of 27 (P< 0.0001). Treatment was well tolerated. CONCLUSION: SPC PER/IND at full doses for 12 months improves endothelial function, structural and functional parameters of the microcirculation, as well as cognitive function in patients with arterial hypertension at high cardiovascular risk. FUNDING: Les Laboratoires Servier.

[Controlled diuretic monotherapy in hypertensive patients: Efficiency and metabolic safety]. / Kontroliruemaya monoterapiya diuretikami u bol'nykh arterial'noi gipertoniei: effektivnost' i metabolicheskaya bezopasnost'.

AIM: To evaluate the antihypertensive efficiency and metabolic effects of controlled monotherapy with hydrochlorothiazide (HCT) and indapamide retard (IR) in hypertensive patients. SUBJECTS AND METHODS: The study included 50 patients with Stage II essential hypertension, grades 1-3 blood pressure (BP) elevation, who received 3-month monotherapy with IR (n=25) or HCT (n=25). Changes were determined in BP, blood lipid, glucose, and potassium levels. The efficiency of antihypertensive therapy was evaluated in the entire group and subgroups of patients identified in accordance with the used diuretic and the presence (n=27) or absence (n=23) of therapy at previous stages. RESULTS: A total of 54% of the patients included in the study achieved target BP after 3 months of therapy. The proportion of individuals with normalized BP was comparable in the HCT and IR groups (52 and 56%, respectively) and in previously treated patients and those who used for the first time antihypertensive drugs (51.8 and 56.5%, respectively). Normalization of systolic and diastolic BPs was achieved in 78 and 58% of the patients, respectively. Target BP was achieved in 94,1%, 42,9% and 16,7% of patients with grades 1,2 and 3 hypertension, respectively. IR proved to be metabolically neutral whereas HCT was found to significantly increase the blood levels of triglycerides and glucose by 15.3% (p<0.05) and 12.2% (p<0.05), respectively. CONCLUSION: Controlled diuretic monotherapy allows BP normalization in more than 50% of the hypertensive patients. HCT and IR have similar antihypertensive efficiency. Because of the negative changes observed in lipid and carbohydrate metabolism with the use of relatively small doses of HCT, IR is a preferential alternative in the long-term treatment of hypertensive patients.

Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin.

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.

An improved LC-MS/MS method for quantitation of indapamide in whole blood: application for a bioequivalence study.

An improved LC-MS/MS method for the quantitation of indapamide in human whole blood was developed and validated. Indapamide-d3 was used as internal standard (IS) and liquid-liquid extraction was employed for sample preparation. LC separation was performed on Synergi Polar RP-column (50 × 4.6 mm i.d.; 4 µm) and mobile phase composed of methanol and 5 mm aqueous ammonium acetate containing 1 mm formic acid (60:40), at flow rate of 1 mL/min. The run time was 3.0 min and the injection volume was 20 µL. Mass spectrometric detection was performed using electrospray ion source in negative ionization mode, using the transitions m/z 364.0 → m/z 188.9 and m/z 367.0 → m/z 188.9 for indapamide and IS, respectively. Calibration curve was constructed over the range 0.25-50 ng/mL. The method was precise and accurate, and provided recovery rates >80% for indapamide and IS. The method was applied to determine blood concentrations of indapamide in a bioequivalence study with two sustained release tablet formulations. The 90% confidence interval for the geometric mean ratios for maximum concentration was 95.78% and for the area under the concentration-time curve it was 97.91%. The tested indapamide tablets (Eurofarma Laboratórios S.A.) were bioequivalent to Natrilix®, according to the rate and extent of absorption.

[Direct comparison of endothelial and metabolic effects of perindopril combination with indapamide retard or hydrochlorothiazide].

OBJECTIVE: Our aim was to compare changes of vascular and metabolic parameters in patients with essential hypertension on treatment with combination of perindopril with either indapamide retard or hydrochlorothiazide. METHODS: The study involved 40 patients who were randomly assigned to perindopril 5-10 mg/day in combination with indapamide retard (P+I) 1.5 mg/day (n = 20) or with hydrochlorothiazide (P+HT) 25 mg/day (n=20). Waist circumference, body mass index, blood lipids and glucose, endothelial function (EF) determined as the change of resistance index after inhalation of salbutamol, arterial stiffness measured as mean pulse wave velocity after sublingual trinitroglycerin (PWVtng) were evaluated at baseline and 6 months thereafter. Vascular responses were calculated from digital pulse waves registered using photoplethysmography. RESULTS: Dynamics of BP after 6 months did not differ significantly between groups. Treatment with combination of P+HT resulted in significant decrease of EF (-24,3%, p<0,05) accompanied by negative changes of triglycerides (+13,4%, p<0,05) and glucose levels (+9,8%, p<0,05), whereas combination of P+I did not affect endothelial function and was metabolically neutral. PWVtng significantly decreases on both regiments of treatment with the trend in favor of P+I combination (-13,4%, p<0,001 versus -9,8%, p<0,01 for P+I and P+HT combinations, respectively). CONCLUSION: Thus, despite the similar BP reduction the combination of ACE-inhibitor--perindopril with indapamide retard possesses more favorable vascular and metabolic effects compared to combination with hydrochlorothiazide that potentially may account for different prognosis of patients with arterial hypertension on long-term treatment.

Genetic polymorphisms of metabolic enzymes and the pharmacokinetics of indapamide in Taiwanese subjects.

To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30~76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.

Pharmacokinetics and bioequivalence study of two indapamide formulations after single-dose administration in healthy Chinese male volunteers.

The pharmacokinetics and relative bioavailability/bioequivalence of 2 formulations of indapamide were assessed in this paper. The study was conducted in 20 healthy Chinese male volunteers according to an open, randomized, single-blind, 2-way crossover study design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 84 h post-dose, and indapamide concentrations in plasma were determined by a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Based on the plasma concentration-time data of each individual in each period, pharmacokinetic parameters, Cmax, AUC0-τ, AUC0-∞ and t1/2, were calculated by non-compartmental analysis. Pharmacokinetic parameters for test and reference formulations were analyzed statistically to assess bioequivalence of the 2 formulations. The values of Cmax, Tmax, t1/2, AUC0-τ, AUC0-∞ for test and reference formulations were 49.53±5.53 and 47.79±4.68 ng/mL, 1.9±0.6 and 2.0±0.5 h, 22.49±5.93 and 23.23±4.48 h, 859.51±160.92 and 840.90±170.62 ng · h/mL, 934.35±190.60 and 919.52±179.74 ng · h/mL, respectively. The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were within the accepted range of 80-125%. It showed that the 2 formulations of indapamide were bioequivalent. Both preparations were well tolerated and no adverse reactions were found throughout the study.

[Vascular effects of perindopril arginine and indapamide fixed combination in patients with arterial hypertension].

The aim of the study was to investigate the dynamics of arterial stiffness and endothelial function parameters under the influence of perindopril arginine and indapamide fixed combination in arterial hypertension (AH) patients. 30 persons with 1-3 degree AH were included into the study. The treatment duration was 24 weeks. Central aortic blood pressure (BP), augmentation pressure and index (AIx), carotid-femoral and carotid-radial pulse wave velocity (PWV), brachial artery endothelium-dependent vasodilatation (EDVD), office and ambulatory BP as well as orthostatic BP falls were evaluated under the influence of selected therapy. 27 patients completed the study protocol. Results showed that aortic systolic BP was significantly reduced by 10.7 mmHg, augmentation pressure - by 3.6 mmHg and AIx - by 6.5%. Carotid-radial PWV decreased by 0.8 m/s. Carotid-femoral PWV did not change. We also revealed the EDVD increase by week 12. The EDVD growth was correlated with degree of aortic systolic BP reduction (r=-0.48, p=0.02). Office and ambulatory BP declined by 15.8/10.0 and 10.0/7.5 mmHg respectively. The target BP <140/90 mmHg was achieved in 20 (74.1%) persons. At the same time the orthostatic hypotension did not rise. Conclusion. We concluded that perindopril arginine/indapamide fixed combination improved vascular function in hypertensive patients by wave reflection reduction, peripheral arterial stiffness lowering and endothelial function improvement.

[The impact of antihypertensive therapy on cerebral hemodynamics in patients with metabolic syndrome].

The aim of this work was the scintigraphic study of brain perfusion and the elucidation of the relationship between daily variations of arterial pressure (AP) and the results of single photon emission computed tomography (SPCT) of the brain in patients with metabolic syndrome (MS). The secondary objective was to estimate effect of combined antihypertensive therapy on cerebral circulation. 24 patients with MS underwent SPCT with 99mTc HMPOA and 24 hr AP monitoring before and 6 mo after therapy with long-acting verapamil combined with slow-release indapamide or enalapril. It was shown that all the patients suffered disturbances of regional cerebral blood flow even in the absence of focal neurological symptoms. Perfusion was especially impaired in the temporal, occipital and superior frontal lobes. The degree of the night-time fall in AP was related to the level of perfusion in the right temporal region (r = -0.5; p = 0.04) which confirms the danger of extreme AD decrease in hypertonics during sleep. Combined antihypertensive therapy has positive influence on cerebral perfusion. Verapamil plus enalapril has more pronounced effect than verapamil plus indapamide on cerebral blood flow in many brain regions.

[Potentialities of medicinal correction of cerebrovascular disturbances in patients with arterial hypertension].

The use of up-to-date diagnostic methods for the examination of 72 patients presenting with grade II-III arterial hypertension and high risk of cardiovascular complications made it possible to estimate the state of brachiocephalic arteries before and after combined antihypertensive therapy that continued during 14 days. The following variables were measured: blood flow rate, peripheral vascular resistance indices at the extra- and intracranial levels, metabolic indices of cerebrovascular responsiveness, and coefficient of variability as an indicator of the cerebrovascular reserve capacity under conditions of antihypertensive treatment. Three antihypertensive therapeutic regimens were employed, viz. lisinopril plus indapamide, bisoprolol plus indapamide, and amlodipine plus indapamide. It was shown that all the three regimen resulted in positive changes in the parameters of blood flow and peripheral vascular resistance. At the same time, the use of amlodipine plus indapamide ensured a more gradual reduction of peripheral vascular resistance and the most pronounced increase of cerebrovascular reserve capacity compared with the two remaining regimens. It is concluded that the parameters of peripheral vascular resistance and metabolic indices of cerebrovascular responsiveness are the most sensitive and informative end points for the pharmacotherapeutic treatment of cerebral hemodynamics in the patients presenting with grade II-III arterial hypertension and high risk of development of cardiovascular complications.

Effects of some antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in rats.

PURPOSE: Indapamide, a non-thiazide antihypertensive diuretic agent, has been widely coadministered with other classes of antihypertensive agents to reach target systolic blood pressure. Indapamide is extensively metabolized by cytochromes P450. Interaction of indapamide and other antihypertensive drugs are unknown. We investigated the effects of other antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in vitro and in vivo. METHODS: Indapamide metabolism was studies in vitro using human liver microsomes pretreated with or without different concentrations of CYP-selective inhibitors and seven major antihypertensive drugs, felodipine, nifedipine, nitrendipine, telmisartan, irbesartan, valsartan and puerarin. Furthermore, the pharmacokinetics of indapamide was determined by HPLC-MS/MS to evaluate the effects of felodipine coadministered on the bioavailability of indapamide in rats in vivo. RESULTS: The Km and Vmax of indapamide metabolism were 114.35 ± 3.47 µM and 23.13 ± 6.61 µmol/g/min. The metabolites of indapamide, hydroxyl-indapamide and dehydrogen-indapamide, were followed. CYP3A4 and CYP2C19 were involved in indapamide metabolism in human live microsomes. In addition, felodipine, nifedipine and nitrendipine significantly inhibited indapamide metabolism with the maximum inhibitory rates of 82.6%, 72% and 95%, respectively. Felodipine significantly elevated indapamide plasma concentration and prolonged its half-life. CONCLUSIONS: Combination therapy of indapamide and felodipine might lead to the alteration of indapamide metabolism and pharmacokinetics. The consequence of such an interaction that may include increased effectiveness and side effect needs to be tudeis in human.

[Selection of rational combinations of indapamide with various of calcium antagonists in patients with arterial hypertension].

We studied 89 patients with II degree arterial hypertension (age 43-67 years). Before and in 24 weeks after therapy we carried out 24-hour monitoring of arterial pressure and Doppler echocardiography. Patients were divided into 2 groups. Combination therapy with indapamide and verapamil retard, indapamide and amlodipine were prescribed to patients of group 1 and 2, respectively. At the background of therapy circadian rhythm was normalized in 82.8 and 76.9% of patients in groups 1 and 2, respectively. In group1 therapy was especially effective in patients with type 1 left ventricular diastolic dysfunction (LVDD), 24-hour nondipper profile, and hyperkinetic type of circulation. In group 2 pronounced changes of parameters were seen in II-III type of LVDD and hypokinetic type of circulation.

Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies.

The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus-tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range.