n-desmethylrosuvastatin and rosuvastatin-lactone

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed and validated for the simultaneous quantification of rosuvastatin (RST), rosuvastatin-5 S-lactone (RSTL), and N-desmethyl rosuvastatin (DM-RST) in human plasma.. Sample was prepared by liquid-liquid extraction with ethyl acetate from 100 μL acidulated buffered plasma. Then analytes were chromatographically separated using an Acquity UPLC HSS T3 column (3.0 mm×100 mm, 1.8 µm) by 0.1% formic acid and gradient acetonitrile at a flow rate of 0.30 mL/min. Three analytes and internal standards (carbamazepine) were eluted in 3.5 min. Mass spectrometry detection was performed through positive ion electrospray ionization (ESI).. The calibration curves for three analytes were linear (R≥0.9987, n=3) within the concentration range of 0.1-50 ng/mL for RST and RSTL, and 0.2-100 ng/mL for DM-RST. Mean extraction recoveries were enhanced by means of acidulated plasma using ammonium acetate of pH 4.0, which ranged within 75.3-98.8% for three analytes. Intra- and inter precision and accuracy were 88.2-96.4%.. This present method was lower LLOQ, less time consuming (3.5 min), less plasma consuming (100 µL) and simpler sample preparation. And it was successfully applied to determine steady state concentrations of RST, RSTL and DM-RST in a clinical study of RST for patients with coronary artery disease (CAD).

Topics: Chromatography, High Pressure Liquid; Coronary Disease; Female; Humans; Lactones; Male; Middle Aged; Rosuvastatin Calcium; Sulfonamides; Tandem Mass Spectrometry

Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin.. The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine.. Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91-1.16]), AUC0-∞ (1.03 [0.89-1.19]) and renal clearance (0.96 [0.85-1.09]) were all within the pre-specified range of 0.8-1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin.. Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cross-Over Studies; Cytochrome P-450 CYP2C19; Drug Interactions; Genotype; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Neoplasm Proteins; Pantoprazole; Polymorphism, Single Nucleotide; Proton Pump Inhibitors; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Young Adult

Cross-study comparisons suggest that systemic exposure (AUC) to rosuvastatin calcium, a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, may be approximately 2-fold higher in Asian subjects living in Asian countries than in white subjects living in Western countries.. This study was conducted to determine the pharmacokinetic characteristics of rosuvastatin and its metabolites after single and multiple doses of rosuvastatin in healthy Chinese subjects living in China.. This was an open-label, ascending single- and multiple-dose study. Subjects were randomly assigned to receive rosuvastatin 5, 10, or 20 mg. Each subject received 1 tablet of the assigned treatment on day 1 and days 4 through 10. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone were measured through 72 hours after administration of single doses and through 96 hours after administration of multiple doses. Blood samples were obtained within 30 minutes before dosing on days 7, 8, and 9 for the assessment of pharmacokinetic parameters at steady state. Noncompartmental pharmacokinetic analysis was performed to determine the C(max) and AUC(0-t) for rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin lactone after single and multiple doses of rosuvastatin. Tolerability assessments were conducted throughout the study.. Of the 36 enrolled subjects, only 1 was female. The mean age of subjects in the rosuvastatin 5-, 10-, and 20-mg groups was 22.4, 21.3, and 22.4 years, respectively. Weight and height ranged from 54 to 85 kg and from 161 to 189 cm, respectively. Geometric mean C(max) values for rosuvastatin after administration of single doses of rosuvastatin 5, 10, and 20 mg were 8.33, 10.76, and 19.17 ng/mL, respectively; the corresponding geometric mean AUC(0-t) values were 57.63, 88.89, and 163.87 ng . h/mL. At steady state, values for C(max) were 8.31, 8.41, and 20.73 ng/mL; the corresponding geometric mean AUC values were 64.87, 77.29, and 178.64 ng . h/mL. After administration of multiple doses of rosuvastatin 5, 10, and 20 mg, the accumulation ratios were 1.23, 0.95, and 1.23, respectively, indicating minimal accumulation of rosuvastatin. Circulating concentrations of N-desmethyl rosuvastatin and rosuvastatin lactone were well below those of rosuvastatin after administration of single and multiple doses of rosuvastatin.. Increases in C(max), AUC(0-t), C(max,ss), and AUC(ss) were observed with increasing single and multiple doses of rosuvastatin 5, 10, and 20 mg. The increase in exposure with increasing doses was lower than would be expected under conditions of strict proportionality. Rosuvastatin exhibited little accumulation on repeated administration. All rosuvastatin doses were well tolerated in these Chinese subjects.

Topics: Administration, Oral; Area Under Curve; Asian People; China; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Male; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Tablets; Young Adult

A simple and sensitive assay was developed and validated for the simultaneous quantification of rosuvastatin acid (RST), rosuvastatin-5S-lactone (RST-LAC), and N-desmethyl rosuvastatin (DM-RST), in buffered human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the three analytes and the corresponding deuterium-labeled (d6) internal standards were extracted from 50 μL of buffered human plasma by protein precipitation. The analytes were chromatographically separated using a Zorbax-SB Phenyl column (2.1 mm × 100 mm, 3.5 μm). The mobile phase comprised of a gradient mixture of 0.1% v/v glacial acetic acid in 10% v/v methanol in water (solvent A) and 40% v/v methanol in acetonitrile (solvent B). The analytes were separated at baseline within 6.0 min using a flow rate of 0.35 mL/min. Mass spectrometry detection was carried out in positive electrospray ionization mode. The calibration curves for all three analytes were linear (R ≥ 0.9964, n = 3) over the concentration range of 0.1-100 ng/mL for RST and RST-LAC, and 0.5-100 ng/mL for DM-RST. Mean extraction recoveries ranged within 88.0-106%. Intra- and inter-run mean percent accuracy were within 91.8-111% and percent imprecision was ≤15%. Stability studies revealed that all the analytes were stable in matrix during bench-top (6 h on ice-water slurry), at the end of three successive freeze and thaw cycles and at -80°C for 1 month. The method was successfully applied in a clinical study to determine the concentrations of RST and the lactone metabolite over 12-h post-dose in patients who received a single dose of rosuvastatin.

Topics: Chromatography, Liquid; Fluorobenzenes; Humans; Lactones; Pyrimidines; Rosuvastatin Calcium; Sensitivity and Specificity; Sulfonamides; Tandem Mass Spectrometry