Population pharmacokinetic modeling to establish the role of P-glycoprotein on ciprofloxacin distribution to lung and prostate following intravenous and intratracheal administration to Wistar rats

Abstract

Ciprofloxacin (CIP) is indicated for clinical treatment of urinary and respiratory tract infections. Poor infection site penetration and consequent insufficient exposure to the antimicrobial agent may be the reason for some therapeutic failures. Ciprofloxacin is reported as a substrate for efflux transporters, such as P-glycoprotein, which could be related to the presence of sub-therapeutic drug concentration at the infection site. In the present work we evaluated CIP pharmacokinetics (PK) in plasma and lung and prostate tissues of Wistar rats after intravenous (i.v.) and intratracheal (i.t.) dosing (7 mg/Kg) in the presence and absence of P-gp inhibitor tariquidar (TAR, 15 mg/Kg). Microdialysis was applied to determine free tissue concentration-time profiles and the obtained data were analyzed by non-compartmental and population PK (popPK) analysis. A sequential strategy was used to develop the popPK model: characterization of CIP PK in tissues (Tissue model) was performed subsequently to CIP PK modeling in plasma (Plasma model). Two and three compartmental models were used to simultaneously characterize plasma concentrations after i.t. and i.v. dosing; the distribution model was developed by separating the central compartment into venous and arterial compartment and by adding lung and prostate; TAR was identified as a significant covariate for clearance and volume of distribution of central compartment as well as for inter-compartmental clearance. Our results indicate an impact of P-gp on plasma PK, likely by acting on renal active secretion of CIP. Regarding CIP exposure in lung and prostate tissues, our results suggest a complex interplay between drug transporters; P-gp inhibition by TAR was likely counterbalanced by the activity of other efflux/influx transporters, which could not be fully characterized by our model.