Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes

Abstract

Inhaled glucocorticoids, such as beclomethasone dipropionate (BDP), are the mainstay treatment of asthma. However, ∼30% of patients exhibit little to no benefit from treatment. It has been postulated that glucocorticoid resistance, or insensitivity, is attributable to individual differences in glucocorticoid receptormediated processes. It is possible that variations in cytochrome P450 3A enzyme-mediated metabolism of BDP may contribute to this phenomenon. This hypothesis was explored by evaluating the contributions of CYP3A4, 3A5, 3A7, and esterase enzymes in the metabolism of BDP in vitro and relating metabolism to changes in CYP3A enzyme mRNA expression via the glucocorticoid receptor in lung and liver cells. . These studies show that CYP3A4 and CYP3A5 metabolize BDP to inactive metabolites and suggest that differences in the expression or function of these enzymes in the lung and/or liver could influence BDP disposition in humans.

Realization of polyaspartamide-based nanoparticles and in vivo lung biodistribution evaluation of a loaded glucocorticoid after aerosolization in mice

“…However, based on the liquid chromatographic retention time, it can be stated that the structure of the unknown metabolite cannot be related to a fatty acid conjugate (Miller-Larsson et al, 1998;Nave et al, 2007) but it may be a hydroxylated and/or dehydrogenated metabolite of BOH (Roberts et al, 2013).…”

Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone

“…6 In this study, a convenience sample of beclomethasone-treated children 2-17 years of age with a physician-confirmed diagnosis of asthma were recruited at Primary Children's Hospital (Salt Lake City, UT). Details of the study design and genotyping have been described previously.…”

“…6 Several CYP3A5 genetic polymorphisms have been shown to alter mRNA expression and enzyme function – the most common is CYP3A5*3 , which codes for an inactive form of CYP3A5. 8 A majority of Caucasians are homozygous for CYP3A5*3 and therefore do not express active CYP3A5, whereas other racial and ethnic groups commonly express the CYP3A5*1 allele, which codes for an active form of CYP3A5.…”

Regulation of CYP3A genes by glucocorticoids in human lung cells

“…In humans, CYP3A4, 3A5, and 3A7 are the primary CYP enzymes involved in glucocorticoid metabolism 8– 11 . CYP3A4 is the most abundant CYP3A enzyme in the liver and intestines 8, 12, 13 , CYP3A5 is more prevalent in the lung than the liver 12, 14– 16 , and CYP3A7 is expressed in fetal liver, but diminishes after birth when CYP3A4 becomes the dominant adult hepatic CYP3A enzyme 17, 18 .…”