Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans
Introduction
A-86929 is a potent and selective agonist to dopamine receptor D-1 and is under evaluation for the treatment of Parkinson's disease (Shiosaki et al., 1996, Brefel et al., 1997) The diacetyl prodrug, ABT-431 (Fig. 1), was synthesized in an attempt to improve the chemical stability and bioavailability of A-86929. The diacetyl prodrug, when administered to humans, was found to immediately convert to A-86929 in the body. However, ABT-431 is subject to extensive ‘first pass’ effect and thus the oral bioavailability is less than 3.5%, when dosed as a solution. Chen et al. (1998) have reported that the bioavailability of ABT-431 in humans can be improved by gingival administration of bioadhesive tablets, which included an effective solubility enhancer for the drug. The intrapulmonary route of administration represents an alternative to oral administration, as well as an effective means of avoiding the hepatic ‘first pass’ clearance (Hoover et al., 1992). In addition, the lung has a large surface area available for absorption. Thus, intrapulmonary administration could be an attractive route for improving the bioavailability of ABT-431. The objectives of this study were: (1) to explore the absorption characteristics of ABT-431 from the lung by intratracheal instillation of the drug solution; (2) to develop a metered dose inhalation (MDI) aerosol of ABT-431 in a non-chlorofluorocarbon propellant, HFC-134a; and (3) to assess the pulmonary delivery and bioavailability of aerosolized drug in dogs and humans.
Section snippets
Materials and equipment
The following materials were used in this study: ABT-431 (lot no. 14-220-AL and 12-177-AL used as reference standard, Pharmaceutical Products Division, Abbott Laboratories); and tetrafluoroethane, HFC-134a (lot 02-933-AL, DuPont). All other chemicals and reagents were either AR or HPLC grade materials and used as received. A Marple–Miller cascade impactor was used to determine the particle size distribution of the inhalation aerosol formulations. Drug assays were performed using an HPLC system
Intratracheal absorption of ABT-431
The mean blood concentrations following a single IV administration of 0.1 mg kg−1 of A-86929 equivalent in groups of six dogs is shown in Fig. 2. Data after intratracheal (IT) instillation of equivalent single doses of drug in groups of six dogs are also shown in the same figure. Estimates of the pharmacokinetic parameters for each of the respective treatments are listed in Table 1. The bioavailability of the IT doses was estimated using area under the plasma concentration versus time curve
Conclusions
Results from this study indicate that ABT-431 is rapidly absorbed following IT instillation to the dog lungs. The absolute pulmonary bioavailability at the dose of 0.1 mg kg−1, against IV controls, was estimated to be about 75%. Furthermore, an HFC-134a based MDI aerosol formulation of ABT-431 was successfully developed. The formulation demonstrated reproducible dose delivery in vitro with approximately 40% of particles delivered from the device less than 5 μm in size. The actuator retention of
Acknowledgements
The authors acknowledge the excellent technical assistance of D. Lee, V. Wu, C. Allexon, H. Buggana, L. Lopez and L. Ruiz in this study. The authors also would like to thank Dr John Cannon and Dr Negar Sadrzadeh for the manuscript preparation.
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