Drug metabolism in the lungs: opportunities for optimising inhaled medicines

TY - JOUR

T1 - Drug metabolism in the lungs: opportunities for optimising inhaled medicines

AU - Enlo-Scott, Zachary

AU - Bäckström, Erica

AU - Mudway, Ian

AU - Forbes, Ben

N1 - Funding Information: E Bäckström is a full-time employee of AstraZeneca, which develops and markets inhaled treatments for respiratory diseases. AstraZeneca reviewed the publication, without influencing the opinions of the authors, to ensure medical and scientific accuracy, and the protection of intellectual property. IS Mudway was partly funded by the National Institute for Health Research Health Protection Research Units (NIHR HPRU) in Environmental Exposures and Health and Chemical and Radiation Threats and Hazards at Imperial College in partnership with Public Health England (PHE). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care or Public Health England. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Publisher Copyright: © 2021 Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4/21

Y1 - 2021/4/21

N2 - Introduction: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development. Areas covered: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. Expert opinion: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a ‘soft drug’ approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

AB - Introduction: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development. Areas covered: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. Expert opinion: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a ‘soft drug’ approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

UR - http://www.scopus.com/inward/record.url?scp=85104813355&partnerID=8YFLogxK

U2 - 10.1080/17425255.2021.1908262

DO - 10.1080/17425255.2021.1908262

M3 - Review article

SN - 1742-5255

VL - 17

SP - 611

EP - 625

JO - Expert Opinion On Drug Metabolism & Toxicology

JF - Expert Opinion On Drug Metabolism & Toxicology

IS - 5

ER -