8,475
Views
0
CrossRef citations to date
0
Altmetric
Review

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

, , & ORCID Icon
Pages 611-625 | Received 15 Feb 2021, Accepted 22 Mar 2021, Published online: 21 Apr 2021

References

  • Courcot E, Leclerc J, Lafitte -J-J, et al. Xenobiotic metabolism and disposition in human lung cell models: comparison with in vivo expression profiles. Drug Metab Dispos. 2012;40(10):1953.
  • Oesch F, Fabian E, Landsiedel R. Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models. Arch Toxicol. 2019;93(12):3419–3489.
  • Taylor G. The absorption and metabolism of xenobiotics in the lung. J Advanced Drug Delivery Reviews. 1990;5(1–2):37–61.
  • Olsson B, Bondesson E, Borgström L, et al. Pulmonary drug metabolism, clearance, and absorption. In: Smyth HDC, Hickey AJ, editors. Controlled pulmonary drug delivery. New York: Springer New York; 2011. p. 21–50.
  • Devereux TR, Domin BA, Philpot RM. Xenobiotic metabolism by isolated pulmonary cells. Pharmacol Ther. 1989;41(1):243–256. 1989/01/01/
  • Foster KA, Oster CG, Mayer MM, et al. Characterization of the A549 cell line as a type II pulmonary epithelial cell model for drug metabolism. Exp Cell Res. 1998;243(2):359–366. 1998/09/15/
  • Hukkanen J, Pelkonen O, Hakkola J, et al. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol. 2002;32(5):391–411. 2002/01/01
  • Jarvis IW, Enlo‐Scott Z, Nagy E, et al. Genotoxicity of fine and coarse fraction ambient particulate matter in immortalised normal (TT1) and cancer‐derived (A549) alveolar epithelial cells. Environmental Molecular Mutagenesis. 2018;59(4):290–301.
  • Piipari R, Savela K, Nurminen T, et al. Expression of CYP1A1, CYP1B1 and CYP3A, and polycyclic aromatic hydrocarbon‐DNA adduct formation in bronchoalveolar macrophages of smokers and non‐smokers. Int J Cancer. 2000;86(5):610–616.
  • Thum T, Erpenbeck VJ, Moeller J, et al. Expression of xenobiotic metabolizing enzymes in different lung compartments of smokers and nonsmokers. Environ Health Perspect. 2006;114(11):1655–1661.
  • Bernauer U, Heinrich-Hirsch B, Tönnies M, et al. Characterisation of the xenobiotic-metabolizing Cytochrome P450 expression pattern in human lung tissue by immunochemical and activity determination. Toxicol Lett. 2006;164(3):278–288. 2006/07/15/
  • Tournel G, Cauffiez C, Billaut-Laden I, et al. Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant. Mutat Res. 2007;617(1):79–89. 2007/04/01/
  • Anttila S, Hukkanen J, Hakkola J, et al. Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol. 1997 Mar;16(3):242–249. PubMed PMID: 9070608; eng.
  • Hukkanen J, Väisänen T, Lassila A, et al. Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther. 2003;304(2):745.
  • Yildiz Y, Gareth W, Markus W, et al. Comparison of rat and human pulmonary metabolism using Precision-cut Lung Slices (PCLS). Drug Metab Lett. 2019;13(1):53–63.
  • Rubin K, Ewing P, Bäckström E, et al. Pulmonary metabolism of substrates for key drug-metabolizing enzymes by human alveolar type II cells, human and rat lung microsomes, and the isolated perfused rat lung model. Pharmaceutics. 2020;12(2):117.
  • Somers GI, Lindsay N, Lowdon BM, et al. A Comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos. 2007;35(10):1797.
  • Van Dyck E, Nazarov PV, Muller A, et al. Bronchial airway gene expression in smokers with lung or head and neck cancer. Cancer Med. 2014;3(2):322–336. 2014/04/01
  • Zuo WL, Shenoy SA, Li S, et al. Ontogeny and biology of human small airway epithelial club cells. Am J Respir Crit Care Med. 2018 Dec 1;198(11):1375–1388. PubMed PMID: 29874100; PubMed Central PMCID: PMCPMC6290945. eng.
  • Howie AF, Forrester LM, Glancey MJ, et al. Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues. Carcinogenesis. 1990 Mar;11(3):451–458. PubMed PMID: 2311189; eng.
  • Wang Y, Spitz MR, Schabath MB, et al. Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study. Lung Cancer. 2003 Apr;40(1):25–32. PubMed PMID: 12660004; eng.
  • Lewis SJ, Cherry NM, Niven RM, et al. GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk. Cancer Lett. 2002;180(2):165–171.
  • Pacifici GM, Franchi M, Bencini C, et al. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica. 1988;18(7):849–856. 1988/01/01
  • Chen C-H. Genetic variations and polymorphisms of metabolic enzymes. In: Xenobiotic metabolic enzymes: bioactivation and antioxidant defenser. Springe, Cham; 2020. p. 155–168.
  • Conway LP, Rendo V, Correia MS, et al. Unexpected acetylation of endogenous aliphatic amines by Arylamine N‐Acetyltransferase NAT2. In: Angewandte chemie international edition. 2020;59(34):14342–14346.
  • Zhang JY, Fen Wang Y, Prakash C. Xenobiotic-metabolizing enzymes in human lung. Curr Drug Metab. 2006;7(8):939–948.
  • Jamaludin J, Marlin N, Wood H, et al. Evaluating the impact of genotype on the relationship between impaired lung growth and chronic exposure to traffic derived pollutants. Eur Respir J. 2013;42(Suppl 57):P3623.
  • Tekpli X, Zienolddiny S, Skaug V, et al. DNA methylation of the CYP1A1 enhancer is associated with smoking‐induced genetic alterations in human lung. Int J Cancer. 2012;131(7):1509–1516.
  • Kuzuya Y, Adachi T, Hara H, et al. Induction of drug‐metabolizing enzymes and transporters in human bronchial epithelial cells by beclomethasone dipropionate. IUBMB Life. 2004;56(6):355–359.
  • Murai T, Reilly CA, Ward RM, et al. The inhaled glucocorticoid fluticasone propionate efficiently inactivates cytochrome P450 3A5, a predominant lung P450 Enzyme. Chem Res Toxicol. 2010;23(8):1356–1364. 2010/08/16
  • Stockmann C, Fassl B, Gaedigk R, et al. Fluticasone propionate pharmacogenetics: CYP3A4• 22 polymorphism and pediatric asthma control. J Pediatr. 2013;162(6):1222–1227.e2. 2013/06/01/
  • Roberts JK, Moore CD, Ward RM, et al. Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes. J Pharmacol Exp Ther. 2013;345(2):308–316. PubMed PMID: 23512537; eng.
  • Stockmann C, Reilly CA, Fassl B, et al. Effect of CYP3A5• 3 on asthma control among children treated with inhaled beclomethasone. J Allergy Clin Immunol. 2015;136(2):505–507.
  • Enlo-Scott Z, Swedrowska M, Forbes B. Epithelial permeability and drug absorption in the lungs. In: Inhaled Medicines. Elsevier; 2021. p. 267–299.
  • Gundert-Remy U, Bernauer U, Blömeke B, et al. Extrahepatic metabolism at the body’s internal–external interfaces. Drug Metab Rev. 2014;46(3):291–324. 2014/08/01
  • Zeldin DC, Foley J, Ma J, et al. CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance. Mol Pharmacol. 1996;50(5):1111–1117.
  • Sarkar MA. Drug metabolism in the nasal mucosa. Pharm Res. 1992;9(1):1–9. 1992/01/01
  • Brittebo EB. Metabolism-dependent activation and toxicity of chemicals in nasal glands. Mutat Res. 1997;380(1):61–75. 1997/10/31/
  • Dahl AR, Hadley WM. Nasal cavity enzymes involved in xenobiotic metabolism: effects on the toxicity of inhalants. Crit Rev Toxicol. 1991;21(5):345–372. 1991/01/01
  • Reed C. Drug metabolism in the nasal cavity: relevance to toxicology. Drug Metab Rev. 1993;25(1–2):173–205.
  • Oliveira P, Fortuna A, Alves G, et al. Drug-metabolizing enzymes and efflux transporters in nasal epithelium: influence on the bioavailability of intranasally administered drugs. Curr Drug Metab. 2016;17(7):628–647.
  • Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/Absorption/Elimination Interplay and Development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22(1):11–23. 2005/01/01
  • Nave R, Fisher R, McCracken N. In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices. Respir Res. 2007;8(1):65.
  • Nonaka T, Nave R, McCracken N, et al. Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549). BMC Pharmacol. 2007;7(1):12. 2007/09/27
  • Nave R, McCracken N. Metabolism of ciclesonide in the upper and lower airways: review of available data. J Asthma Allergy. 2008;1:11–18. PubMed PMID: 21436981; eng.
  • Pearce RE, Leeder JS, Kearns GL. BIOTRANSFORMATION OF FLUTICASONE: IN VITRO CHARACTERIZATION. Drug Metab Dispos. 2006;34(6):1035.
  • Tunek A, Sjödin K, Hallström G. Reversible formation of fatty acid esters of budesonide, an antiasthma glucocorticoid, in human lung and liver microsomes. Drug Metab Dispos. 1997;25(11):1311–1317.
  • Sahasranaman S, Issar M, Hochhaus G. METABOLISM OF MOMETASONE FUROATE AND BIOLOGICAL ACTIVITY OF THE METABOLITES. Drug Metab Dispos. 2006;34(2):225.
  • Teng XW, Cutler DJ, Davies NM. Mometasone furoate degradation and metabolism in human biological fluids and tissues. Biopharm Drug Dispos. 2003;24(8):321–333. 2003/11/01
  • Eaton EA, Walle UK, Wilson HM, et al. Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells. Br J Clin Pharmacol. 1996;41(3):201–206. 1996/03//. PubMed PMID: 8866919; eng.
  • Evans ME, Shenfield GM, Thomas N, et al. The pharmacokinetics of rimiterol in man. Xenobiotica. 1974;4(11):681–692.
  • Winkler J, Hochhaus G, Derendorf H. How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc. 2004;1(4):356–363.
  • Mukker JK, Singh RSP, Derendorf H. Ciclesonide: a pro-soft drug approach for mitigation of side effects of inhaled corticosteroids. J Pharm Sci. 2016;105(9):2509–2514. 2016/09/01/
  • Sato H, Nave R, Nonaka T, et al. In vitro metabolism of ciclesonide in human nasal epithelial cells. Biopharm Drug Dispos. 2007;28(1):43–50. 2007/01/01
  • Nave R, Meyer W, Fuhst R, et al. Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther. 2005;18(6):390–396. 2005/12/01/
  • Wieslander E, Delander E-L, Järkelid L, et al. Pharmacologic importance of the reversible fatty acid conjugation of budesonide studied in a rat cell line in vitro. Am J Respir Cell Mol Biol. 1998;19(3):477–484. PubMed PMID: 9730876
  • Borchard G, Cassará ML, Roemelé PE, et al. Transport and local metabolism of budesonide and fluticasone propionate in a human bronchial epithelial cell line (Calu‐3). J Pharm Sci. 2002;91(6):1561–1567.
  • Hemmerling M, Nilsson S, Edman K, et al. Selective nonsteroidal glucocorticoid receptor modulators for the inhaled treatment of pulmonary diseases. J Med Chem. 2017;60(20):8591–8605. 2017/10/26
  • Nassr N, Huennemeyer A, Herzog R, et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N‐oxide in healthy subjects. Br J Clin Pharmacol. 2009;68(4):580–587.
  • Huennemeyer A, Hauns B, David M, et al. Pharmacokinetics and safety of Roflumilast, a once-daily, oral, selective PDE4 inhibitor, and its active metabolite Roflumilast N-oxide in healthy subjects. J Allergy Clin Immunol. 2004;113(2, Supplement):S222. 2004/02/01/
  • Lahu G, Nassr N, Hünnemeyer A. Pharmacokinetic evaluation of roflumilast. Expert Opin Drug Metab Toxicol. 2011;7(12):1577–1591. 2011/12/01
  • Murad HA, Habib HS, Rafeeq MM, et al. Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. Experimental Biology and Medicine. 2017;242(5):516–526.
  • Éy S, Amaro MI, De Almeida GS, et al. Development of a new formulation of roflumilast for pulmonary drug delivery to treat inflammatory lung conditions. Int J Pharm. 2018;550(1):89–99. 2018/10/25/
  • Sun D. Remdesivir for Treatment of COVID-19: combination of pulmonary and iv administration may offer aditional benefit. Aaps J. 2020;22(4):1–6.
  • Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396):396.
  • Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381–385.
  • Yan V, Muller F. Advantages of the parent nucleoside GS-441524 over remdesivir for Covid-19 treatment. ACS Med Chem Lett. 2020;11(7):1361–1366.
  • Yang K. What do we know about remdesivir drug interactions? Clin Transl Sci. 2020;13(5):842–844.
  • Baginski L, Tachon G, Falson F, et al. Reverse transcription polymerase chain reaction (RT-PCR) analysis of proteolytic enzymes in cultures of human respiratory epithelial cells. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2011;24(2):89–101.
  • Forbes B, Wilson C, Gumbleton M. Temporal dependence of ectopeptidase expression in alveolar epithelial cell culture: implications for study of peptide absorption. Int J Pharm. 1999;180(2):225–234.
  • Morita T, Yamamoto A, Takakura Y, et al. Improvement of the pulmonary absorption of (Asu 1, 7)-eel calcitonin by various protease inhibitors in rats. Pharm Res. 1994;11(6):909–913.
  • Kobayashi S, Kondo S, Juni K. Study on pulmonary delivery of salmon calcitonin in rats: effects of protease inhibitors and absorption enhancers. Pharm Res. 1994;11(9):1239–1243.
  • Hussain A, Arnold JJ, Khan MA, et al. Absorption enhancers in pulmonary protein delivery. J Control Release. 2004;94(1):15–24.
  • Woods A, Andrian T, Sharp G, et al. Development of new in vitro models of lung protease activity for investigating stability of inhaled biological therapies and drug delivery systems. Eur J Pharm Biopharm. 2020;146:64–72. 2020/01/01/
  • Frederiksen B, Pressler T, Hansen A, et al. Effect of aerosolized rhDNase (Pulmozyme®) on pulmonary colonization in patients with cystic fibrosis. Acta Paediatrica. 2006;95(9):1070–1074.
  • Guichard MJ, Leal T, Vanbever R. PEGylation, an approach for improving the pulmonary delivery of biopharmaceuticals. Curr Opin Colloid Interface Sci. 2017;31:43–50. 2017/09/01/
  • King PT, Sharma R, O’Sullivan KM, et al. Deoxyribonuclease 1 reduces pathogenic effects of cigarette smoke exposure in the lung. Sci Rep. 2017;7(1):12128. 2017/09/21
  • Griese M, Scheuch G. Delivery of Alpha-1 antitrypsin to airways. Ann Am Thorac Soc. 2016;13(Supplement 4):S346–S351.
  • Brantly M, Stocks J, Rouhani F, et al. Inhaled alpha-1-antitrypsin restores lower respiratory tract protease-anti-protease homeostasis and reduces inflammation in alpha-1 antitrypsin deficient individuals: a phase 2 clinical study using inhaled kamada-api. C74. ADVANCES IN TRANSLATIONAL COPD: American Thoracic Society. 2017;A7677–A7677.
  • Barrecheguren M, Miravitlles M. Treatment with inhaled α1-antitrypsin: a square peg in a round hole? Eur Respir J. 2019;54(5):1901894.
  • Stolk J, Tov N, Chapman KR, et al. Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD. Eur Respir J. 2019;54(5):5.
  • Morales JO, Fathe KR, Brunaugh A, et al. Challenges and future prospects for the delivery of biologics: oral mucosal, pulmonary, and transdermal routes. Aaps J. 2017;19(3):652–668. 2017/05/01
  • Martinelli F, Balducci AG, Kumar A, et al. Engineered sodium hyaluronate respirable dry powders for pulmonary drug delivery. Int J Pharm. 2017;517(1):286–295. 2017/01/30/
  • Mantaj J, Abu-Shams T, Enlo-Scott Z, et al. Role of the basement membrane as an intestinal barrier to absorption of macromolecules and nanoparticles. Mol Pharm. 2018;15(12):5802–5808. 2018/12/03
  • Kumar A, Terakosolphan W, Hassoun M, et al. A biocompatible synthetic lung fluid based on human respiratory tract lining fluid composition. Pharm Res. 2017;34(12):2454–2465.
  • Surendrakumar K, Martyn GP, Hodgers ECM, et al. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J Control Release. 2003;91(3):385–394. 2003/09/04/
  • Guerreiro F, Pontes JF, Am RDC, et al. Spray-drying of konjac glucomannan to produce microparticles for an application as antitubercular drug carriers. Powder Technol. 2019;342:246–252. 2019/01/15/
  • Islam N, Dmour I, Taha MO. Degradability of chitosan micro/nanoparticles for pulmonary drug delivery. Heliyon. 2019;5(5):e01684. 2019/05/01/
  • Juhász C, Muzik O, Lu X, et al. Quantification of tryptophan transport and metabolism in lung tumors using PET. J Nucl Med. 2009 Mar;50(3):356–363. PubMed PMID: 19223408; PubMed Central PMCID: PMCPMC2784997. eng.
  • Faubert B, Li KY, Cai L, et al. Lactate metabolism in human lung tumors. Cell. 2017;171(2):358–371.e9. 2017/10/05/
  • Mittal S, Chowhan RK, Singh LR. Macromolecular crowding: macromolecules friend or foe. Biochim Biophys Acta Gen Subj. 2015;1850(9):1822–1831. 2015/09/01/
  • Silverstein TP, Slade K. Effects of macromolecular crowding on biochemical systems. J Chem Educ. 2019;96(11):2476–2487. 2019/11/12
  • Kim JS, Yethiraj A. Effect of macromolecular crowding on reaction rates: a computational and theoretical study. Biophys J. 2009;96(4):1333–1340. 2009/02/18/
  • Ward JK, Dow J, Dallow N, et al. Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man — no evidence of enantioselective lung metabolism. Br J Clin Pharmacol. 2000;49(1):15–22. 2000/01/01
  • Aridgides DS, Mellinger DL, Armstrong DA, et al. Functional and metabolic impairment in cigarette smoke-exposed macrophages is tied to oxidative stress. Sci Rep. 2019;9(1):1–11.
  • Hussain T, Al-Attas OS, Al-Daghri NM, et al. Induction of CYP1A1, CYP1A2, CYP1B1, increased oxidative stress and inflammation in the lung and liver tissues of rats exposed to incense smoke. Molecular and Cellular Biochemistry. 2014;391(1–2):127–136.
  • Ehrmann S, Schmid O, Darquenne C, et al. Innovative preclinical models for pulmonary drug delivery research. Expert Opin Drug Deliv. 2020;17(4):463–478. 2020/04/02
  • Castell JV, Teresa Donato M, Gómez-Lechón MJ. Metabolism and bioactivation of toxicants in the lung. The in vitro cellular approach. Exp Toxicol Pathol. 2005;57:189–204. 2005/07/22/
  • Cohen GM. Pulmonary metabolism of foreign compounds: its role in metabolic activation. Environ Health Perspect. 1990;85:31–41.
  • Okona-Mensah KB, Battershill J, Boobis A, et al. An approach to investigating the importance of high potency polycyclic aromatic hydrocarbons (PAHs) in the induction of lung cancer by air pollution. Food Chem Toxicol. 2005;43(7):1103–1116. 2005/07/01/
  • Dahl AR, Gerde P. Uptake and metabolism of toxicants in the respiratory tract. Environ Health Perspect. 1994;102(suppl 11):67–70.
  • Chapter HE. 38 - metabolism of pesticides. In: Krieger R, editor. Hayes’ Handbook of Pesticide Toxicology (Third Edition). New York: Academic Press; 2010. p. 893–921.
  • Gram TE. Chemically reactive intermediates and pulmonary xenobiotic toxicity. Pharmacol Rev. 1997;49(4):297.
  • Li L, Carratt S, Hartog M, et al. Human CYP2A13 and CYP2F1 mediate naphthalene toxicity in the lung and nasal mucosa of CYP2A13/2F1-humanized mice. Environ Health Perspect. 2017;125(6):067004.
  • Parkinson OT, Teitelbaum AM, Whittington D, et al. Species differences in microsomal oxidation and glucuronidation of 4-ipomeanol: relationship to target organ toxicity. Drug Metab Dispos. 2016;44(10):1598–1602. PubMed PMID: 27468999; eng.
  • Wiek C, Schmidt EM, Roellecke K, et al. Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol. Biochem J. 2015;465(1):103–114. PubMed PMID: 25247810; eng.
  • Foth H. Role of the lung in accumulation and metabolism of xenobiotic compounds — implications for chemically induced toxicity. Crit Rev Toxicol. 1995;25(2):165–205. 1995/01/01
  • Owen K. Regulatory toxicology considerations for the development of inhaled pharmaceuticals. Drug Chem Toxicol. 2013;36(1):109–118. 2013/01/01
  • Seo J, Huh D. Chapter 7 - Microphysiological models of human organs: a case study on microengineered lung-on-a-chip systems. In: Borenstein JT, Tandon V, Tao SL, editors. Microfluidic cell culture systems. Second. Elsevier.187–208. 2019.
  • Yamamoto E, Taquahashi Y, Kuwagata M, et al. Visualizing the spatial localization of ciclesonide and its metabolites in rat lungs after inhalation of 1-μm aerosol of ciclesonide by desorption electrospray ionization-time of flight mass spectrometry imaging. Int J Pharm. 2021;595:120241. 2021/02/15/
  • Dexter A, Steven RT, Patel A, et al. Imaging drugs, metabolites and biomarkers in rodent lung: a DESI MS strategy for the evaluation of drug-induced lipidosis. Anal Bioanal Chem. 2019;411(30):8023–8032. 2019/12/01