In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Nave, Ruediger; Fisher, Ron; McCracken, Nigel W.

doi:10.1186/1465-9921-8-65

Cited by 39 publications

(32 citation statements)

References 30 publications

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“…In vitro studies in human tissue and in vivo studies in rats have reported that des-CIC forms reversible conjugates with fatty acids, which are pharmacologically inactive and do not bind to the glucocorticoid receptor [7,[13][14][15]. The findings regarding the metabolism of CIC derived from in vitro and animal studies have yet to be confirmed by in vivo studies in human subjects.…”

mentioning

confidence: 75%

“…These in vivo findings confirm the two major metabolic pathways of ciclesonide in the human lung: the rapid, on-site conversion of ciclesonide to des-CIC and the conjugation of des-CIC with fatty acids, in particular oleic acid. Such findings have previously been shown in vitro in human tissue and in vivo in animals [13][14][15]. • • ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ therefore, a slight offset for different time-points in these patients was used for better illustration.…”

Section: Discussionmentioning

confidence: 99%

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Deposition and metabolism of inhaled ciclesonide in the human lung

Nave¹,

Watz²,

Hoffmann³

et al. 2010

Eur Respir J

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Ciclesonide is an inhaled corticosteroid, administered as a prodrug via a metereddose inhaler. Following deposition in the lung, ciclesonide is hydrolysed by esterases to form the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Formation of des-CIC, as well as reversible esterification of des-CIC with fatty acids, has been demonstrated in vitro. The aim of this study was to investigate the in vivo metabolism of ciclesonide in the human lung.This single-dose, open-label, nonrandomised study was performed in 20 patients undergoing planned lung surgery for treatment of malignant pulmonary lesions. Patients inhaled a single dose of 1,280 mg ciclesonide at various time-points between 2 and 24 h prior to lung tissue resection. The concentration of ciclesonide, des-CIC and fatty acid conjugates of des-CIC in tissue samples was determined. Serum samples for pharmacokinetic analysis were taken at several time-points after inhalation.The pharmacokinetics in serum indicated that the inhalation by the patients was adequate. Metabolites (des-CIC, des-CIC oleate and des-CIC palmitate) were detected in the resected central and peripheral lung tissues. A substantial portion of ciclesonide was already activated to des-CIC at the first time-point of tissue analysis.Activation of ciclesonide and formation of des-CIC fatty acid conjugates was confirmed in vivo in the human lung.

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mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Deposition and metabolism of inhaled ciclesonide in the human lung

Nave¹,

Watz²,

Hoffmann³

et al. 2010

Eur Respir J

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“…The four compounds produced were two monopropionates, that is, beclomethasone 17-monopropionate (2) and beclomethasone 21-monopropionate (3), one epoxy (5), and one depropionated derivative (4). Compound (4) was already reported as pharmacologically inactive, and compound (2) was pharmacologically active (Nave, Fisher, McCracken, 2007), whereas compound (3) was reported as pharmacologically inactive compound (Würthwein, Rohdewald, 1990). It is expected that the new metabolites formed may have more anti-inflammatory activity; better therapeutic profile, safety, and efficacy; and least resistance and can be employed in the treatment of asthma as that of the parent compound.…”

Section: Discussionmentioning

confidence: 99%

Microbial biotransformation of beclomethasone dipropionate by Aspergillus niger

Ahmad

Khaliq

Madni

et al. 2014

Braz. J. Pharm. Sci.

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In the present research, the steroidal anti-asthmatic drug beclomethasone dipropionate was subjected to microbial biotransformation by Aspergillus niger. Beclomethasone dipropionate was transformed into various metabolites first time from microbial transformation. New drug metabolites produced can act as new potential drug molecules and can replace the old drugs in terms of safety, efficacy, and least resistance. They were purified by preparative thin layer chromatography technique, and their structures were elucidated using modern spectroscopic techniques, such as 13 C NMR, 1 H NMR, HMQC, HMQC, COSY, and NOESY, and mass spectrometry, such as EI-MS. Four metabolites were purified: (i) beclomethasone 17-monopropionate, (ii) beclomethasone 21-monopropionate, (iii) beclomethasone, and (iv) 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 21-propionate.Uniterms: Anti-asthmatics. Aspergillus niger/use in biotransformation. Beclomethasone dipropionate/ microbial biotransformation. Steroids/microbial transformation. Biotransformation.Na pesquisa presente o fármaco esteróide antiasmático dipropionato de beclometasona foi submetido à biotransformação microbiana pelo Aspergillus niger. O dipropionato de beclometasona foi transformado, pela primeira vez, em metabólitos variados por biotransformação microbiana. Novos metabólitos do fármaco produzidos podem agir como novas moléculas potenciais e podem substituir os fármacos antigos em questão de segurança, eficácia e mínima resistência. Eles foram purificados por cromatografia em camada delgada preparativa e as suas estruturas foram elucidadas usando técnicas espectroscópicas modernas, como 13 C NMR, 1 H NMR; HMQC; HMQC; COSY, NOESY e espectrometria de massas, por exemplo, EI-MS. Purificaram-se quatro metabólitos, denominados (i) 17-monopropionato de beclometasona; (ii) 21-monopropionato de beclometasona: (iii) beclometasona e (iv) 21-propionato de 9beta,11beta-epoxi-17,21-diidroxi-16beta-metilpregna-1,4-dieno-3,20-diona.Unitermos: Antismáticos. Aspergillus niger/uso em biotransformação. Dipropionato de beclomentasona/ biotransformação microbiana. Esteróide/biotransformação microbiana. Biotransformação.

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“…The activity of these metabolites is less than 1% of that of the parent compound, and they do not contribute further to the therapeutic effect of budesonide (Silverman & Otley, 2011). In vitro studies of the phase II metabolism of budesonide have demonstrated that it undergoes sulfation by cytosolic sulfotransferase enzyme 1A1 (Meloche et al, 2002); studies in lung tissue slices have also demonstrated the formation of fatty acid esters from budesonide (Nave et al, 2007). Budesonide is eliminated in the urine (60%) and faeces (40%) as metabolites (US Food and Drug Administration, 2009).…”

Section: Introductionmentioning

confidence: 99%

In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes

et al. 2017

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Abstract1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter-or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied.

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In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Cited by 39 publications

References 30 publications

Deposition and metabolism of inhaled ciclesonide in the human lung

Deposition and metabolism of inhaled ciclesonide in the human lung

Microbial biotransformation of beclomethasone dipropionate by Aspergillus niger

In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes

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