To investigate the impact of two different routes of administration on the lung and systemic exposure of drugs designed for local delivery to the lung.
Methods:
In our comparative studies, similar lung doses of three different drugs were administered to rodents by both intratracheal instillation and inhaled delivery.
Results:
An obvious but unexpected difference in the exposure was observed. Immediately after the dose, the initial plasma concentration was much higher whereas the initial fraction of the lung dose in the lung was clearly lower for the instillation compared with the inhaled delivery. There was also a difference in the tolerability for one of the drugs when the same lung dose was administered and the inhaled dose was, in contrast to the instilled dose, tolerated by the mice.
Conclusions:
A plausible explanation for the observed but contrary to expected difference is that the drugs leaked from the lung into the systemic circulation already during the instillation procedure due to its invasive nature.
BrainJD, KnudsonDE, SorokinSP, et al.Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ Res, 1976; 11(1):13–33; doi: 10.1016/0013-9351(76)90107-9
2.
PritchardJN, HolmesA, EvansJC, et al.The distribution of dust in the rat lung following administration by inhalation and by single intratracheal instillation. Environ Res, 1985; 36(2):268–297; doi: 10.1016/0013-9351(85)90025-8
3.
ColthorpeP, FarrSJ, TaylorG, et al.The pharmacokinetics of pulmonary-delivered insulin: A comparison of intratracheal and aerosol administration to the rabbit. Pharm Res, 1992; 9(6):764–768; doi: 10.1023/a:1015851521551
4.
VogelP, RiveraVR, PittML, et al.Comparison of the pulmonary distribution and efficacy of antibodies given to mice by intratracheal instillation or aerosol inhalation. Lab Anim Sci, 1996; 46(5):516–523.
5.
ZecchiR, TrevisaniM, PittelliM, et al.Impact of drug administration route on drug delivery and distribution into the lung: An imaging mass spectrometry approach. Eur J Mass Spectrom (Chichester), 2013; 19(6):475–482; doi: 10.1255/ejms.1254
6.
CossíoU, Gómez-VallejoV, FloresM, et al.Preclinical evaluation of aerosol administration systems using Positron Emission Tomography. Eur J Pharm Biopharm, 2018; 130:59–65; doi: 10.1016/j.ejpb.2018.05.037
7.
YangL, FeuchtingerA, MöllerW, et al.Three-dimensional quantitative co-mapping of pulmonary morphology and nanoparticle distribution with cellular resolution in nondissected murine lungs. ACS Nano, 2019; 13(2):1029–1041; doi: 10.1021/acsnano.8b07524
8.
DriscollKE, CostaDL, HatchG, et al.Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: Uses and limitations. Toxicol Sci, 2000; 55(1):24–35; doi: 10.1093/toxsci/55.1.24
9.
YiD, PriceA, Panoskaltsis-MortariA, et al.Measurement of the distribution of aerosols among mouse lobes by fluorescent imaging. Anal Biochem, 2010; 403(1–2):88–93; doi: 10.1016/j.ab.2010.04.005
10.
YanjunW, KotzerCJ, MakrogiannisS, et al.A noninvasive [99mTc]DTPA SPECT/CT imaging methodology as a measure of lung permeability in a guinea pig model of COPD. Mol Imaging Biol, 2011; 13(5):923–929; doi: 10.1007/s11307-010-0423-9
11.
HammGR, BäckströmE, BrüllsM, et al.Revealing the regional localization and differential lung retention of inhaled compounds by mass spectrometry imaging. J Aerosol Med Pulm Drug Deliv, 2020; 33(1):43–53; doi: 10.1089/jamp.2019.1536
12.
CreutzenbergO, KochW, HansenT, et al.Comparison of inhalation and intratracheal instillation as testing methods for characterisation of Granular Biopersistent Particles (GBP). Federal Institute for Occupational Safety and Health, 2018; doi: 10.21934/baua:bericht20180823
13.
SmithKR, LeonardD, McDonaldJD, et al.Inflammation, mucous cell metaplasia, and Bcl-2 expression in response to inhaled lipopolysaccharide aerosol and effect of rolipram. Toxicol Appl Pharmacol, 2011; 253(3):253–260; doi: 10.1016/j.taap.2011.04.001
14.
LiuF, LiW, PauluhnJ, et al.Lipopolysaccharide-induced acute lung injury in rats: Comparative assessment of intratracheal instillation and aerosol inhalation. Toxicol, 2013; doi: 10.1016/j.tox.2012.12.020
15.
Hasegawa-BabaY, KubotaH, TakataA, et al.Intratracheal instillation methods and the distribution of administered material in the lung of the rat. J Toxicol Pathol, 2014; 27(3 + 4):197–204; doi: 10.1293/tox.2014-0022
16.
OkaY, MitsuiM, KitahashiT, et al.A reliable method for intratracheal instillation of materials to the entire lung in rats. J Toxicol Pathol, 2006; 19(2):107–109; doi: 10.1293/tox.19.107
17.
PerryMWD, BjörhallK, BoldP, et al.Discovery of AZD8154, a dual PI3Kγδ inhibitor for the treatment of asthma. J Med Chem, 2021; 64(12):8053–8075; doi: 10.1021/acs.jmedchem.1c00434
18.
PinkertonJW, PreiteS, PirasA, et al.PI3Kγδ inhibition suppresses key disease features in a rat model of asthma. Respir Res, 2024; 25(1); doi: 10.1186/s12931-024-02814-1
19.
BoydBJ, BergströmCAS, VinarovZ, et al.Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems. Eur J Pharm Sci, 2019; 137:104967; doi: 10.1016/j.ejps.2019.104967
20.
BrüllsM, OagS, KarlssonCA, et al.Same lung deposited dose in dog dosing a fine and coarse aerosol indicates no difference in intranasal filtration. Int J Pharm, 2022; 624:121977; doi: 10.1016/j.ijpharm.2022.121977
21.
SadiqMW, AsimusS, BelvisiMG, et al.Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kγδ dual inhibitor targeting airway inflammatory disease. Br J Clin Pharmacol, 2022; 88(1):260–270; doi: 10.1111/bcp.14956
22.
PerryMWD, BjörhallK, BonnB, et al.Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration. J Med Chem, 2017; 60(12):5057–5071; doi: 10.1021/acs.jmedchem.7b00401
23.
KusM, IbragimowI, Piotrowska-KempistyH. Caco-2 cell line standardization with pharmaceutical requirements and in vitro model suitability for permeability assays. Pharmaceutics, 2023; 15(11):2523; doi: 10.3390/pharmaceutics15112523
24.
CarlingCJ, BrüllsM. Milling of poorly soluble crystalline drug compounds to generate appropriate particle sizes for inhaled sustained drug delivery. Int J Pharm, 2021; 593:120116; doi: 10.1016/j.ijpharm.2020.120116
25.
ManF, TangJ, SwedrowskaM, et al.Imaging drug delivery to the lungs: Methods and applications in oncology. Adv Drug Deliv Rev, 2023; 192:114641; doi: 10.1016/j.addr.2022.114641
26.
BondessonE, BengtssonT, NilssonLE, et al.Site of deposition and absorption of an inhaled hydrophilic solute. Br J Clin Pharmacol, 2007; 63(6):722–731; doi: 10.1111/j.1365-2125.2006.02835.x
27.
SherAC, StacyMR, ReynoldsSD, et al.In vivo detection of pulmonary mucociliary clearance: Present challenges and future directions. Eur Respir Rev, 2024; 33(173):240073; doi: 10.1183/16000617.0073-2024
28.
Daley-YatesPT, BakerRC. Systemic bioavailability of fluticasone propionate administered as nasal drops and the aqueous nasal spray formulations. Br. J. Pharmacol, 2001; 51:103–105; doi: 10.1046/j.1365-2125.2001.01325.x
29.
AllenA, DownG, NewlandA, et al.Absolute bioavailability of intranasal fluticasone furoate in healthy subjects. Clin Ther, 2007; 29(7):1415–1420; doi: 10.1016/j.clinthera.2007.07.028
30.
HochhausG. Pharmacokinetic/pharmacodynamic profile of mometasone furoate nasal spray: Potential effects on clinical safety and efficacy. Clin Ther, 2008; 30(1):1–13; doi: 10.1016/j.clinthera.2008.01.005
31.
Daley-YatesPT. A reply. Br. J. Pharmacol, 2001; 52:458–460; doi: 10.1046/j.0306-5251.2001.01431.x-i1
32.
MartinAR. Regional deposition: Targeting. J Aerosol Med Pulm Drug Deliv, 2021; 34(1):1–10; doi: 10.1089/jamp.2021.29033.am
