Beclomethasone dipropionate is a second-generation synthetic corticosteroid agent and a diester of beclomethasone, which is structurally similar to [dexamethasone]. It is a prodrug of an active metabolite beclomethasone 17-monopropionate (17-BMP) which acts on the glucocorticoid receptor. anti-inflammatory drug, an anti-asthmatic drug, a prodrug and an anti-arrhythmia drug. Subbstrate of Arylacyl amidase but not of carboxylesterases and cholinesterases. During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP)
Title: Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use Qian Y, Melchert PW, Markowitz JS Ref: Chemico-Biological Interactions, :110228, 2022 : PubMed
Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC(50) values estimated as 8.98 and 36.8 microM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally taken CBD was expected to be of no clinical relevance.
