International Journal of Pharmaceutics 358 (2008) 96–101 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Evaluation of gatifloxacin penetration into skeletal muscle and lung by microdialysis in rats Leandro Tasso a , Clarissa C. Bettoni a , Laura K. Oliveira b , Teresa Dalla Costa a,b,∗ a Programa de P´ os-Graduac ¸˜ ao em Ciˆ encias Farmacˆ euticas, Porto Alegre, RS, Brazil b Faculdade de Farm´ acia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil article info Article history: Received 10 December 2007 Received in revised form 19 February 2008 Accepted 20 February 2008 Available online 4 March 2008 Keywords: Gatifloxacin Skeletal muscle penetration Lung penetration Microdialysis Wistar rats abstract This study aimed to investigate gatifloxacin distribution into skeletal muscle and lung interstitial fluid by microdialysis and to correlate free tissue and free plasma levels of the drug. Microdialysis recoveries were determined in vitro by extraction efficiency and retrodialysis at 80, 160 and 400ng/ml resulting in 33.5 ± 1.3%, 33.1 ± 1.2%, 31.8 ± 2.7% and 31.4 ± 2.6%, 33.1 ± 2.2%, 30.6 ± 3.3%, respectively. In vivo recovery by retrodialysis in Wistar rats’ skeletal muscle and lung were 29.1 ± 1.0% and 30.7 ± 1.4%, respectively. The recovery was constant and independent on the method or media used. Gatifloxacin tissue pene- tration was investigated after intravenous dosing of 6mg/kg to Wistar rats. Free skeletal muscle, lung and plasma profiles were virtually super imposable resulting in similar area under the curve (AUC 0–9 ) of 3888 ± 734 ng h/ml, 4138 ± 1071 ng h/ml and 3805 ± 577 ng h/ml, respectively (˛ = 0.05). The tissue distri- bution factors were 1.02 and 1.08 for muscle and lung relative to plasma. In conclusion, free plasma levels are a good surrogate for gatifloxacin active levels at the infection site. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Pharmacokinetic studies of antimicrobial drugs most often rely on plasma data. However, since most infections take place in tis- sues extra cellular fluids, free antimicrobial concentrations in the interstitial space at the infection site are responsible for the antibac- terial effect (Marchand et al., 2005). Unless an antimicrobial is able to both sufficiently penetrate the target site and maintain an appropriate concentration in the infected tissue, it may fail to be clinically effective despite documented in vitro susceptibility of the involved pathogen (Joukhadar et al., 2001). Suboptimal target site concentrations of antimicrobial drugs may have important clinical implications being a potential explanation for therapeutic failure (Brunner et al., 2000; Joukhadar et al., 2001) besides triggering bac- terial resistance (Hyatt et al., 1995). Although at steady-state drug levels are in equilibrium between plasma and tissue, drug pene- tration is not similar among different tissues and the free levels at the biophase must be known viewing to optimize antimicrobial therapy. Community-acquired pneumonia (CAP) has an incidence of 3–5 cases per 1000 people and a mortality rate of 5–15% in hospital- ∗ Corresponding author at: Universidade Federal do Rio Grande do Sul, Programa de P ´ os-Graduac ¸˜ ao em Ciˆ encias Farmacˆ euticas, Av. Ipiranga 2752, Porto Alegre, RS 90.610-000, Brazil. Tel.: +55 51 3308 5418; fax: +55 51 3308 5437. E-mail address: teresadc@farmacia.ufrgs.br (T.D. Costa). ized patients (Kaplan et al., 2002). Antibacterial therapy is usually indicated because of the risk of serious complications such as bac- teremia and meningitis if the bacterial infection is left untreated (Liu, 2004). Despite a broad armamentarium of antimicrobials available to treat the disease, pneumonia remains the seventh leading cause of death in the United States (Minino and Smith, 2001). The management of CAP is becoming progressively com- plicated due to the expanding spectrum of causative organisms, the rising prevalence of resistance to antimicrobial agents and the increasing population of patients of advanced age and with comorbidities (Marrie, 1999; Ros ´ on et al., 2001). Streptococcus pneu- moniae is the most significant bacterial pathogen associated with community-acquired respiratory tract infections (File, 2006). Res- piratory fluoroquinolones, such as gatifloxacin, are antimicrobials highly active against the pathogens most frequently implicated in CAP. Traditionally, tissue biopsies, saliva sampling or blister fluid measurements have been used to measure drug tissue concentra- tions. Drug concentrations at the respiratory tract infections can be studied by assaying whole lung tissue, sputum, respiratory secre- tions, pleural fluid and by sampling epithelial lining fluid, especially bronchoalveolar lavage (BAL) (Brunner and Langer, 2006). BAL is currently the most often employed sampling technique for phar- macokinetic research in lung. However, calculation of the true concentration in BAL may sometimes be imprecise (Allegranzi et al., 2000), leading to overestimation of actual active concentra- tions in the extracellular fluid. The general limitations of BAL are 0378-5173/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2008.02.023