Simultaneous determination of ezetimibe and simvastatin in rat plasma by stable-isotope dilution LC-ESI–MS/MS and its application to a pharmacokinetic study

Abstract

A simple, sensitive and specific liquid chromatography–tandem mass spectrometry method was developed for simultaneous quantification of ezetimibe and simvastatin in rat plasma. The deuterium isotopes: ezetimibe d4 and simvastatin d6 were used as internal standards for ezetimibe and simvastatin, respectively. MS/MS detection involved a switch of electron spray ionization mode from negative to positive at retention time 3.01 min. Samples were extracted from plasma by liquid–liquid extraction using tertiary butyl methyl ether. Chromatographic separation was achieved with Agilent Eclipse XBD-C18 column using mobile phase that consisted of a mixture of ammonium acetate (pH4.5; 10 mM)–acetonitrile (25:75 v/v). The method was linear and validated over the concentration range of 0.2–40.0 ng/mL for simvastatin and 0.05–15.0 ng/mL for ezetimibe. The transitions selected were m/z 408.3→271.1 and m/z 412.0→275.10 for ezetimibe and ezetimibe d4, and m/z 419.30→285.20 and m/z 425.40→199.20 for simvastatin and simvastatin d6. Intra- and inter-batch precisions for ezetimibe were 1.6–14.8% and 2.1–13.4%; and for simvastatin 0.94–9.56% and 0.79–12%, respectively. The proposed method was sensitive, selective, precise and accurate for the quantification of ezetimibe and simvastatin simultaneously in rat plasma. The method was successfully applied to a pharmacokinetic study by oral co-administration of ezetimibe and simvastatin in SD rats.

Cetyl‐alcohol‐reinforced hollow fiber solid/liquid‐phase microextraction and HPLC–DAD analysis of ezetimibe and simvastatin in human plasma and urine

“…The detected concentration of EZT was 2.71 μg L −1 (RSD 3.7%) and that of SIV was 2.44 μg L −1 (RSD 6.1%). These results for real plasma sample analyses indicate satisfactory agreement with previous pharmacokinetic reported results (Karanam et al, ; Munaga et al, ).…”

“…Despite the widespread use of EZT–SIV fixed‐dose combination, the literature survey reveals that only limited analytical methods have been published on the simultaneous determination of these components in plasma specimens (Karanam, Katakam, Chandu, Hwisa, & Adiki, ; Munaga, Valluru, Bonga, Rao, & Sharma, ). The sample pretreatment techniques employed in these methods are liquid–liquid (LLE; Karanam et al, ) and solid‐phase extraction (SPE; Munaga et al, ), prior to liquid chromatography with mass spectrometry (LC–MS) analysis. These conventional techniques (LLE and SPE) generally require multistep protocols that are time‐consuming and use large volumes of high‐purity organic solvents (Lee, Lee, Rasmussen, & Pedersen‐Bjergaard, ).…”

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

“…21 All of the formulations showed a higher plasma concentration of the drug as compared with the drug powder. 3 In particular, the total plasma concentrations with SESD were significantly increased as compared with the drug powder in the initial time period (0.5-1.0 hours). Moreover, there were no significant differences in the plasma concentration at each time point among solid SNEDDS, SMSD, and SESD.…”

“…2,3 The US Food and Drug Administration has accepted ezetimibe as a new medication. 4 Ezetimibe is a class II molecule as per the Biopharmaceutics Classification System due to its poor water solubility and high permeability.…”

Simultaneous quantitation of rosuvastatin and ezetimibe in human plasma by LC–MS/MS: Pharmacokinetic study of fixed‐dose formulation and separate tablets

“…Similarly, EZE has been determined in different biological fluids like human plasma (Li, Liu, Jia, Li, & Yu, ; Oliveira et al, ; Ucakturk, Ozaltin, & Kaya, ) and human serum, urine and feces (Oswald, Scheuch, Cascorbi, & Siegmund, ) using gas chromatography–mass spectrometry (Ucakturk et al, ) and liquid chromatography–tandem mass spectrometry (LC–MS/MS) (Li et al, ; Oliveira et al, ; Oswald et al, ). Some other methods describe estimation of EZE and its glucuronide metabolite (Bahrami et al, ; Guo, Wang, He, Qiu, & Jiang, ), and EZE with other drugs (Abdelbary & Nebsen, ; El‐Bagary, Elkady, El‐Sherif, & Kadry, ; Karanam, Katakam, Chandu, Hwisa, & Adiki, ; Munaga, Valluru, Bonga, Rao, & Sharma, ). Simultaneous determination of ROS and EZE in human plasma has been the subject of several reports (Ashfaq, Ahmad, Khan, & Mustafa, ; Kang et al, ; Kim, An, Kim, & Shin, ; Min, Park, Jung, Chang, & Kim, ; Varghese & Ravi, ).…”