Date Published: June 6, 2019
Publisher: Public Library of Science
Author(s): Rui Zhao, Qing Wang, Xin-Xin Hu, Tong-Ying Nie, Xin-Yi Yang, Cong-Ran Li, Xi Lu, Xiukun Wang, Jian-Dong Jiang, Jing Pang, Xue-Fu You, Hua Zhou.
Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen.
Antibacterial drug resistance, an urgent global crisis, is seriously threatening public health and social stability. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA), a major cause of hospital and community-associated infections, has become the focus of novel antibacterial development. Gemifloxacin (pKa1 = 5.53, pKa2 = 9.53; LogP = 1.7313; molecular weight 389.3809)  is a broad-spectrum fluoroquinolone antibacterial with relatively high antimicrobial activity against Gram-positive bacteria. Compared with other quinolones, gemifloxacin shows a better inhibitory effect on topoisomerase IV, a primary target of Staphylococcus aureus .
Most PK studies on antimicrobial agents are based on the measurement of total plasma concentration. However, antibacterial activity can be exerted only by the drugs of the unbound fraction in the interstitial fluid where the infections occur. In local infection, PK profiles for plasma and target tissues may be markedly different. Therefore, the prediction of antimicrobial efficacy based on plasma PK data may result in overestimation of the dose regimen and failure of antibiotic therapy. Regulatory authorities such as the FDA and European Agency for the Evaluation of Medicinal Products advocate that the concentrations of antibacterial at the target site should be determined.
In conclusion, this validated method was successfully applied to quantify free gemifloxacin concentrations in rat plasma and thigh muscle and provides the possibility to investigate the real concentrations of gemifloxacin in different parts of the body simultaneously, which would shed light on the dosing regimen optimization of gemifloxacin. The significantly lower free gemifloxacin concentrations in skeletal muscle than in plasma in MRSA-infected rats suggested that the dosing regimen according to drug levels in plasma to the treatment of local tissue infection is unreasonable.