Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Chem Biol Interact. 2022 Dec 1;368:110228. doi: 10.1016/j.cbi.2022.110228. Epub 2022 Oct 22.
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 Δ-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 values estimated as 8.98 and 36.8 μM, 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 administered CBD was expected to be of no clinical relevance.
倍氯米松二丙酸盐（BDP）是一种吸入用糖皮质激素，用于成人和儿童的哮喘维持治疗。BDP 是一种前药，在肺部被水解为其主要活性代谢物倍氯米松-17-单丙酸盐（17-BMP）后被激活，17-BMP 可以进一步失活为倍氯米松（BOH）。尚未确定促成这些过程的特定水解酶，因此需要进行研究，以便更好地评估药物相互作用（DDI）的风险，并更好地管理药物的疗效和全身毒性。在本研究中，使用人肺 S9（HLuS9）和重组羧酸酯酶 1（CES1）S9 研究了 BDP 的肺部代谢。通过采用相对活性方法，我们检验了 CES1 是主要参与酶的假设。在具有选择性酯酶抑制剂的测定中进行了对其他水解酶的评估。此外，由于吸入大麻的娱乐和医疗用途不断增加，评估了 BDP 与 Δ-四氢大麻酚（THC）和大麻二酚（CBD）之间的 DDI 潜力。在体外时间依赖性抑制测定中进行了 DDI 机制研究，并利用提出的模型进行了进一步解释。在 HLuS9 中，BDP 几乎完全有效地代谢为 17-BMP，然后以低得多的速率转化为 BOH。CES1 被发现是一个次要贡献者，仅占 HLuS9 中 BDP 代谢的 1.4％，而芳基乙酰胺脱乙酰酶可能是主要参与的酶。THC 和 CBD 均以可逆方式抑制 HLuS9 介导的 BDP 水解，报道的 IC 值估计分别为 8.98 和 36.8 μM。我们提出的模型表明，同时吸入大麻香烟中的 THC 会使肺部 17-BMP 的暴露量适度降低，而口服 CBD 的作用预计无临床相关性。
