Abstract
Sirolimus is a hydrophobic macrolide compound that has been used for long-term immunosuppressive therapy, prevention of restenosis, and treatment of lymphangioleiomyomatosis. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of sirolimus in both porcine whole blood and lung tissue. Blood and lung tissue homogenates were deproteinized with acetonitrile and injected into the LC-MS/MS system for analysis using the positive electrospray ionization mode. The drug was separated on a C18 reversed phase column with a gradient mobile phase (ammonium formate buffer (5 mM) with 0.1% formic acid and acetonitrile) at 0.2 mL/min. The selected reaction monitoring transitions of m/z 931.5 → 864.4 and m/z 809.5 → 756.5 were applied for sirolimus and ascomycin (the internal standard, IS), respectively. The method was selective and linear over a concentration range of 0.5–50 ng/mL. The method was validated for sensitivity, accuracy, precision, extraction recovery, matrix effect, and stability in porcine whole blood and lung tissue homogenates, and all values were within acceptable ranges. The method was applied to a pharmacokinetic study to quantitate sirolimus levels in porcine blood and its distribution in lung tissue following the application of stents in the porcine coronary arteries. It enabled the quantification of sirolimus concentration until 2 and 14 days in blood and in lung tissue, respectively. This method would be appropriate for both routine porcine pharmacokinetic and bio-distribution studies of sirolimus formulations.
Highlights
Sirolimus is a hydrophobic macrolide compound produced by a strain of the bacterium Streptomyces hygroscopicus in Easter Island [1]
With the positive ionization mode, sirolimus and IS exhibited ammonium adducts [M + NH4 ]+ at m/z 931.5 and 809.5, respectively, which are frequently observed in ammonia-mediated ionization mass spectra of compounds with oxygen groups in their structures [33]
Thereafter, the selected reaction monitoring (SRM) quantitative analyses were performed with m/z 931.5 → 864.4 for sirolimus and m/z 809.5 → 756.5 for the IS
Summary
Sirolimus ( known as rapamycin) is a hydrophobic macrolide compound produced by a strain of the bacterium Streptomyces hygroscopicus in Easter Island [1]. It was first isolated and developed as an antifungal drug with potent anticandidal activity [2]. In terms of pharmacokinetic properties, sirolimus in solution is rapidly absorbed from the human gastrointestinal tract and reaches the maximal blood concentration after 2 h [6] It distributes extensively into red blood cells (95%) [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
