title: Prediction of the pharmacokinetics and tissue distribution of levofloxacin in humans based on an extrapolated PBPK model.
abstract: This study developed a physiologically based pharmacokinetic (PBPK) model in intraabdominally infected rats and extrapolated it to humans to predict the levofloxacin pharmacokinetics and penetration into tissues. Twelve male rats with intraabdominal infections induced by Escherichia coli received a single dose of 50 mg/kg body weight of levofloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480 and 1440 min after injection, respectively. A PBPK model was developed in rats and extrapolated to humans using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration-versus-time profile of levofloxacin in rats, C max was 23.570 μg/ml at 5 min after intravenous injection, and t1/2 was 2.38 h. The plasma concentration and kinetics in humans were predicted and validated by the observed data. Levofloxacin penetrated and accumulated with high concentrations in the heart, liver, kidney, spleen, muscle and skin tissues in humans. The predicted tissue-to-plasma concentration ratios in abdominal viscera were between 1.9 and 2.3. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict the drug pharmacokinetics and penetration in humans. Levofloxacin had good penetration into the liver, kidney and spleen as well as other tissues in humans. This pathological model extrapolation may provide a reference for the study of antiinfective PK/PD. In our study, levofloxacin penetrated well into abdominal organs. Also ADR monitoring should be implemented when using levofloxacin.
authors.affiliation: Pharmacy Department, Tianjin First Center Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China. zlq0713@aliyun.com.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Pharmacy Department, Tianjin First Center Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pharmacy Department, Tianjin First Center Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
authors.forename: Jianlei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The 153 Central Hospital of the Chinese People's Liberation Army, Henan, 450000, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Dong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D064704:Levofloxacin / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D064704:Levofloxacin
keywords: Extrapolation; Human; Levofloxacin; PBPK model; Pharmacokinetics