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Development of a No...
Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds
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- Bäckström, Erica (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden,Translational PKPD
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- Lundqvist, Anders (författare)
- AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden
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- Boger, Elin (författare)
- AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.; Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England
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- Svanberg, Petter (författare)
- AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden
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- Ewing, Pär (författare)
- AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden
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- Hammarlund-Udenaes, Margareta (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Translational PKPD
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- Fridén, Markus (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden,Translational PKPD
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(creator_code:org_t)
- Elsevier BV, 2016
- 2016
- Engelska.
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 105:2, s. 838-845
- Relaterad länk:
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http://jpharmsci.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Pharmacokinetics and Drug Therapy
- Farmakokinetik och läkemedelsterapi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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