title: Simultaneous Semimechanistic Population Analyses of Levofloxacin in Plasma, Lung, and Prostate To Describe the Influence of Efflux Transporters on Drug Distribution following Intravenous and Intratracheal Administration.
abstract: Levofloxacin (LEV) is a broad-spectrum fluoroquinolone used to treat pneumonia, urinary tract infections, chronic bacterial bronchitis, and prostatitis. Efflux transporters, primarily P-glycoprotein (P-gp), are involved in LEV's tissue penetration. In the present work, LEV free lung and prostate interstitial space fluid (ISF) concentrations were evaluated by microdialysis in Wistar rats after intravenous (i.v.) and intratracheal (i.t.) administration (7 mg/kg of body weight) with and without coadministration of the P-gp inhibitor tariquidar (TAR; 15 mg/kg administered i.v.). Plasma and tissue concentration/time profiles were evaluated by noncompartmental analysis (NCA) and population pharmacokinetics (popPK) analysis. The NCA showed significant differences in bioavailability (F) for the control group (0.4) and the TAR group (0.86) after i.t. administration. A four-compartment model simultaneously characterized total plasma and free lung (compartment 2) and prostate (compartment 3) ISF concentrations. Statistically significant differences in lung and prostate average ISF concentrations and levels of kidney active secretion in the TAR group from those measured for the control group (LEV alone) were observed. The estimated population means were as follows: volume of the central compartment (V1), 0.321 liters; total plasma clearance (CL), 0.220 liters/h; TAR plasma clearance (CLTAR), 0.180 liters/h. The intercompartmental distribution rate constants (K values) were as follows: K12, 8.826 h(-1); K21, 7.271 h(-1); K13, 0.047 h(-1); K31, 7.738 h(-1); K14, 0.908 h(-1); K41, 0.409 h(-1); K21 lung TAR (K21LTAR), 8.883 h(-1); K31 prostate TAR (K31PTAR), 4.377 h(-1). The presence of P-gp considerably impacted the active renal secretion of LEV but had only a minor impact on the efflux from the lung following intratracheal dosing. Our results strongly support the idea of a role of efflux transporters other than P-gp contributing to LEV's tissue penetration into the prostrate.
authors.affiliation: Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Estevan Sonego
authors.initials: ES
authors.lastname: Zimmermann
authors.affiliation: Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: João Victor
authors.initials: JV
authors.lastname: Laureano
authors.affiliation: Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Camila Neris
authors.initials: CN
authors.lastname: Dos Santos
authors.affiliation: Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida at Lake Nona, Orlando, Florida, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Center for Pharmacometrics & Systems Pharmacology, College of Pharmacy, University of Florida at Lake Nona, Orlando, Florida, USA.
authors.forename: Chakradhar V
authors.initials: CV
authors.lastname: Lagishetty
authors.affiliation: College of Pharmacy, Federal University of São João del-Rei, Divinópolis, Brazil.
authors.forename: Whocely Victor
authors.initials: WV
authors.lastname: de Castro
authors.affiliation: Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Brazil teresadc@farmacia.ufrgs.br.
authors.forename: Teresa
authors.initials: T
authors.lastname: Dalla Costa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D061605:Administration, Intravenous; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D002138:Calibration; D004333:Drug Administration Routes; D064704:Levofloxacin / Q000008:administration & dosage / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics*; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D064704:Levofloxacin