Losartan Acid Research Articles

Bioequivalence study of two Losartan tablet formulations with special emphasis on cardiac safety

To study the bioequivalence of Losartan Potassium Tablets 50 mg manufactured by Micro Labs Ltd. India to Cozaar® Tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in normal healthy adult subjects under fasting condition along with the comparative safety evaluation of both treatments. The in vitro dissolution studies were carried out on 12 units each of test and reference products using the paddle method and dissolution media like water, 0.1 N hydrochloric acid with pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. An open label, randomized, two-treatment, two-period, two-sequence, crossover bioequivalence study with a washout period of 7 days was conducted in 60 healthy Indian male subjects. Serial blood samples were collected after drug administration in each study period. Plasma concentrations of losartan and losartan acid were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of losartan and losartan acid were determined using a non compartmental model. Occurrence of adverse events, change in systolic blood pressure, diastolic blood pressure, heart rate and QT interval from the baseline to 3.50 h post dose were studied and compared between the two treatments as safety parameters. The in vitro study proved the essential similarity of both the formulations as evident from the similarity factor of > 50% in all the dissolution media. The ratios for geometric least square means and 90% confidence intervals were within the acceptance criteria of 80% to 125% for log transformed C(max), AUC(0-t) and AUC(0-∞) for losartan. No statistically significant difference between the two treatments was observed for either of the safety parameters. The test product Losartan Potassium tablets 50 mg manufactured by Micro Labs Limited, India was bioequivalent to Cozaar® tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in terms of rate and extent of absorption. Both treatments were well tolerated and had similar non significant effect on the safety parameters.

Simultaneous determination of losartan, losartan acid and amlodipine in human plasma by LC-MS/MS and its application to a human pharmacokinetic study

Introduction: A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric assay method has been developed and fully validated for simultaneous quantification of losartan and its active metabolite, losartan carboxylic acid, and amlodipine in human plasma. Irbesartan was used as an internal standard. Materials and Methods: The analytes were extracted from human plasma samples by solidphase extraction technique using Oasis HLB cartridges, (Waters Corporation, Mumbai, India). The reconstituted samples were chromatographed on a C18 column by using an 85:15, v/v mixture of methanol and 0.1% v/v formic acid as the mobile phase at a flow rate of 1.0mL/min. A detailed validation of the method was performed as per the FDA guidelines. Results: The calibration curves obtained were linear (r≥0.99) over the concentration range of 0.5-1000ng/mL for losartan and for its active metabolite losartan acid and 0.05-10.1ng/mL for amlodipine. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. Conclusions: A run time of 2.5min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies.

Rapid determination of losartan and losartan acid in human plasma by multiplexed LC–MS/MS

A rapid LC-MS/MS method has been developed and validated for the determination of losartan (LOS) and its metabolite losartan acid (LA) (EXP-3174) in human plasma using multiplexing technique (two HPLC units connected to one MS/MS). LOS and LA were extracted from human plasma by SPE technique using Oasis HLB cartridge without evaporation and reconstitution steps. Hydroflumethiazide (HFTZ) was used as an internal standard (IS). The analytes were separated on Zorbax SB C-18 column. The mass transition [M-H] ions used for detection were m/z 421.0 --> 127.0 for LOS, m/z 435.0 --> 157.0 for LA, and m/z 330.0 --> 239.0 for HFTZ. The proposed method was validated over the concentration range of 2.5-2000 ng/mL for LOS and 5.0-3000 ng/mL for LA with correlation coefficient > or = 0.9993. The overall recoveries for LOS, LA, and IS were 96.53, 99.86, and 94.16%, respectively. Total MS run time was 2.0 min/sample. The validated method has been successfully used to analyze human plasma samples for applications in 100 mg fasted and fed pharmacokinetic studies.

Simultaneous quantification of losartan and active metabolite in human plasma by liquid chromatography–tandem mass spectrometry using irbesartan as internal standard

A simple and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method employing electronspray ionization was developed and validated for quantification of losartan and its carboxylic acid metabolite in human plasma using irbesartan as internal standard (IS). Following a simple pretreatment procedure, the analytes were separated using a gradient mobile phase on reverse phase C18 column. Selected reaction monitoring was specific for losartan, losartan acid and irbesartan. The method validation demonstrated the specificity, lower limit of quantification, accuracy and precision of measurements. The assay exhibited a linear dynamic range of 2.0–400ng/mL for losartan and 1.85–370ng/mL for losartan acid. A run time of 3.5min for each sample made it possible to analyze more than 200 samples per day. The validated method has been successfully used to analyze human plasma samples for application in bioavailability/bioequivalence studies.

Comparative bioavailability of two losartan formulations in healthy human volunteers after a single dose administration

To compare the bioavailability of two potassic losartan immediate release tablet (50 mg) formulations (Losartan from Laboratórios Cristália Ltd., Brazil, as a test formulation and Cozaar from Merck Sharp & Dohme Farmacêutica Ltd., Brazil, as a reference formulation) in 25 volunteers of both sexes. The study was conducted in an open, randomized, 2-period crossover design and a 1-week washout period. Plasma samples were obtained over a 24-hour interval. The concentrations of losartan and its active metabolite losartan acid were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using a selected ion monitoring method. From the losartan and losartan acid plasma concentrations vs. time curves the following pharmacokinetic parameters were obtained: AUClast, AUC0-inf and Cmax. The geometric mean and respective 90% confidence interval (CI) of Losartan/Cozaar losartan percent ratios were 92.9% (82.2-105.0%) for Cmax, 99.0% (92.5-105.9%) for AUClast, and 99.1% (92.7-105.8%) for AUC0-inf. Furthermore, the geometric mean and respective 90% CI of Losartan/Cozaar losartan acid percent ratios were 98.5% (91.5-106.0%) for Cmax, 97.9% (93.3 102.7%) for AUClast, and 98.1% (93.6-102.9%) for AUC0-inf. Since the 90% CI for Cmax, AUClast and AUC0-inf were within the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that the potassic losartan immediate release 50 mg tablet was bioequivalent to the Cozaar immediate release 50 mg tablet, according to both the rate and extent of absorption. While there were no significant differences in the bioequivalence assessed by either losartan or losartan acid, future bioequivalence studies on losartan may be performed by quantifying losartan alone as the parent compounds are more discriminative.

The Effect of AST‐120 on the Single‐Dose Pharmacokinetics of Losartan and Losartan Acid (E‐3174) in Healthy Subjects

AST-120 is an orally administered adsorbent used to slow the progression of chronic kidney disease (CKD). This was a randomized, open-label, 5-way crossover study to assess the effect of AST-120 on the pharmacokinetics of losartan and its active metabolite (E-3174) in healthy subjects. Losartan (100 mg) was administered alone under fasting (A) and fed (B) conditions, and results were compared when AST-120 (3 g thrice daily for 2 days) was administered 60 minutes after (C), 30 minutes prior to (D), and 30 minutes after (E) losartan. Plasma concentrations of losartan and E-3174 were assayed by high-performance liquid chromatography with mass spectrometry detection. Under fed conditions, treatment C had no significant effect on the AUC(0-t) and Cmax of losartan and E-3174. Treatments D and E resulted in a marked decrease in Cmax of losartan and E-3174. Therefore, administration of AST-120 60 minutes after losartan under fed conditions may be preferred over other dosing regimens for CKD patients.