Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

Abstract

Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6b-hydroxylation and Δ 6-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Δ 6 -flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.

Corticosteroid and Cortisol Serum Levels Following Intra‐articular Triamcinolone Acetonide Lumbar Facet Joint Injections

“…The long terminal elimination half‐life following spinal injection of triamcinolone and the suppressive effects of the drug on the HPA axis could potentiate the risk for developing serious drug–drug interactions in select patient populations. Triamcinolone is a substrate for the cytochrome P450 3A4 (CYP3A4) family of enzymes . Hypercortisolism, otherwise referred to as Cushing's syndrome, and suppression of the HPA axis have been reported following use of triamcinolone in patients receiving drugs known to inhibit cytochrome CYP3A4.…”

Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials

“…Our study revealed no detectable budesonide, 16α-hydroxy prednisolone, or budesonide-palmitate in the gray or white matter of the brain in this premature lamb model study, which may be evidence of a favorable safety profile, although the sample size is small. Furthermore, budesonide is extensively metabolized by cytochrome P450 (CYP) 3A enzymes in vitro [34]. However, cytochrome P450 3A4 activity level is low in premature newborns that progressively increases to adult activity [35].…”

Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes

“…Experiments were performed on six biologic replicates (n 5 6), mRNA copy number was determined from a standard curve, and the data normalized to the copy number for B2M. (Foe et al, 1998a(Foe et al, ,b, 2000aDaley-Yates et al, 2001;Mutch et al, 2007) were detected in all incubations lacking esterase inhibitors; formation of [M1-M3] , and comparable metabolites produced by CYP3A enzymes using other structurally similar glucocorticoids (Moore et al, 2013). The MS/MS spectrum for [M4] (m/z 537 at 20 minutes; Fig.…”

“…4A), consistent with desaturation of BDP. Cytochrome P450 3A enzymes dehydrogenate the C-6/7 bond of multiple steroid molecules and other glucocorticoids (Teitelbaum et al, 1981;Edsbacker et al, 1987;Moore et al, 2013). Therefore, [M5] is presumed to be D 6 -BDP.…”