Biopharmaceutical characterization of nebulized antimicrobial agents in rats: 1. Ciprofloxacin, moxifloxacin, and grepafloxacin

Abstract

The aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF, and 19.1 ± 10.5 for GRX (means ± standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (VELF), passive diffusion clearance (QELF), and active efflux clearance (CLout) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.

FIG 1

Structural model used for simultaneous PK analysis of plasma and ELF drug concentrations following i.v. administration or intratracheal administration in nebulized form of MXF, where the V_c is the volume of the central compartment, V_ELF is the volume of the ELF compartment, which was fixed at 30 × 10⁻⁶ liters kg⁻¹, and V_P1 and V_P2 are the volumes of peripheral compartments. CL_T corresponds to total plasma clearance, Q₁ and Q₂ are distribution clearances between the central compartment and peripheral compartments, Q_ELF is the diffusion clearance between the central compartment and ELF, CL_out is the transfer efflux clearance between the central compartment and ELF compartment, and F_aero is the systemic bioavailability after aerosol administration. The same model was used for CIP, except for the absence of peripheral compartment 2.

FIG 2

Mean ± SD concentrations of CIP, MXF, and GRX estimated in ELF [C_{ELF(estimated)}] at 0.5 h, 2 h, 4 h, and 6 h after i.v. administration or administration intratracheally of nebulized forms at doses of 7.5 mg kg⁻¹ for CIP and MXF and 5 mg kg⁻¹ for GRX. NS, not significantly different; **, P < 0.001.

FIG 3

Concentration-time profiles of CIP and MXF following i.v. administration (a and c) and administraion of the nebulized form (b and d) in plasma (closed symbols and solid line) and in ELF (open symbols and dashed line), predicted from simultaneous PK modeling of plasma and ELF data. Symbols represent means ± SD concentrations measured in plasma and ELF.

FIG 4

C_{ELF(estimated)}/C_ELF(actual) ratio predicted from equation 7, as a function of volume of lysed cells during BAL and K values determined for CIP, MXF, and GRX.