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chemical research in toxicology
acs publications
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Abstract: |
The global burden of bacterial infection and antimicrobial resistance increases the demand to associate more than one
antibiotic to fight life-threatening bacteria. Therefore, there is a great necessity to develop simple and sensitive methods for routine
analysis of clinical samples. Therapeutic drug monitoring, bioequivalence, and pharmacokinetic studies are essential to ensure drug
efficiency and safety. Herein, therefore, the first ecofriendly liquid chromatography −tandem mass spectrometry (LC−MS/MS)
method was developed and fully validated for simultaneous determination of a commonly combined antibiotic for methicillinresistant
Staphylococcus aureus (MRSA), vancomycin (VCM) and gentamicin (GTM), in rat plasma after parenteral administration.
VCM and GTM were extracted from plasma sample using acetonitrile (ACN)/0.1% TFA-induced protein precipitation followed by
the separation on an Agilent Eclipse Plus ODS (3 mm × 100 mm, 3.5 μm) column using water-enriched mobile phase consisting of
water containing 0.1% THF/ACN (85:15, v/v%) at flow rates of 0.30 mL min−1. The mass spectrometry parameters were optimized,
and multiple reaction monitoring (MRM) in positive ion mode of two transitions was utilized for quantification of precursor to
product ion at m/z 725.5 → 144 and 100.1 for VCM as [M + 2H]2+, 478.3 → 322.2 and 156.9 for GTM, and 586.3 → 162.9 and
425.3 for amikacin (AMK) internal standard, as [M + H]+. The current method has been validated as per U.S. FDA bioanalytical
guidelines in terms of linearity, accuracy, precision, selectivity, recovery, matrix effects, and stability. The method was linear in the
range of 1−2000 ng mL−1 and 1−1000 ng mL−1 with detection limits (S/N of 3) of 0.18 and 0.09 ng mL−1 for VCM and GTM,
respectively. The selectivity and high sensitivity allow the current method to succeed in the study of pharmacokinetic parameters and
drug−drug interaction between VCM and GTM after single-dose administration. VCM increased plasma clearance and elimination
rate constant of GTM when coadministered and GTM also too. The change of serum chemistry analysis and significant elevation of
creatinine and BUN indicate an alteration in kidney function in group III in those given the combined antibiotics. Our finding
illustrated the nephrotoxicity of the two drugs when associated. The ecofriendly, simplicity, and rapidity of the current study made it
a promising method for high-throughput biomonitoring in clinical samples.
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