Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Peter Byron

Abstract

Tobramycin disposition following airway administration was evaluated by meta-analysis of human data in the literature and, experimentally, using a realistic ex vivo model, the isolated perfused rat lung preparation (IPRL). Pulmonary bioavailability of inhaled tobramycin in published studies was re-evaluated separately for CF and healthy adults, with the drug’s intrinsic pharmacokinetic (PK) parameters obtained from intravenous (IV) studies in the literature. While large variations in tobramycin’s clearance precluded accurate assessment of its bioavailability, the results were indicative of substantial pulmonary absorption, in spite of its hydrophilic and poly cationic properties. To explore its disposition kinetics and mechanisms following airway administration, tobramycin absorption was investigated as a function of dose in the IPRL. The cumulative fraction of the administered tobramycin dose reaching the perfusate versus time, was bi-exponential and dose-dependent, unlike that of the marker solutes fluorescein and mannitol, both of which showed first-order and dose-independent kinetics. A kinetic model that incorporated lung tissue binding (or sequestration) alongside passive absorption was employed successfully to describe the aminoglycoside’s disposition in the IPRL following airway administration. Tobramycin’s absorption was fast with the first-order absorption rate constants (0.065-0.070 min-1) close to those seen with fluorescein (0.076 min-1), but a dose-, and concentration-dependent slow onset tissue binding prolonged its presence in the rat lung. Binding was confirmed by independent dynamic dialysis experiments using sliced lung prepared from the intact IPRL, immediately following airway administration using an identical technique as that used in tobramycin absorption studies. Dosing solution osmolality and pH had negligible effects on the drug’s disposition in the IPRL, when these were investigated over experimental ranges that could be used clinically. While tobramycin itself was found to accelerate mannitol’s absorption, and thus affect airway epithelial integrity when administered at high doses, the effect was undetectable at a dose level in rat lungs that was believed to produce airway concentrations corresponding to those in human patients using TOBI®. These findings may partly explain the apparent success of inhaled tobramycin therapy in the treatment of pulmonary infections.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2013

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