Department of Pharmacy, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Department of Pharmacy, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; Pharmaceutical Research and Technology Institute, Kindai University, Osaka 577-8502, Japan; Antiaging Center, Kindai University, Osaka 577-8502, Japan.
Eur J Pharm Sci. 2022 Jul 1;174:106193. doi: 10.1016/j.ejps.2022.106193. Epub 2022 Apr 18.
Acyl glucuronides (AGs) are considered to cause idiosyncratic drug toxicity (IDT), and evaluating the chemical instability of AGs may be useful for predicting the IDT risk of novel drug candidates. However, AGs show variations in their chemical instability, degree of formation, and enzymatic hydrolysis. Therefore, we evaluated the degree of AG formation, enzymatic hydrolysis, and chemical instability in liver microsomes and their relationship with IDT risk. Nonsteroidal anti-inflammatory drugs (NSAIDs) were classified into three categories in terms of their IDT risk as parent drugs: safe (SA), warning (WA), and withdrawn (WDN). To evaluate the enzymatic and non-enzymatic degradation of AG, the parent drugs were incubated with rat liver microsomes in the absence or presence of AG hydrolase inhibitors. The degree of AG formation and disappearance was considered as the rate constant. For all NSAIDs investigated, the number of AGs formed notably increased following addition of AG hydrolase inhibitors. Particularly, AG was produced by WDN drugs at a lower level than that produced by WA and SA drugs in the absence of AG hydrolase inhibitors but was significantly increased after adding AG hydrolase inhibitors. The rate constants of AG formation and non-enzymatic AG disappearance did not significantly differ among the WDN, WA, and SA drugs, whereas the rate constant of enzymatic AG disappearance of WDN drugs tended to be higher than those of WA and SA drugs. In conclusion, we evaluated the enzymatic degradation and chemical instability of AG by simultaneously producing it in liver microsomes. This method enables evaluation of AG degradation without preparing AG. Moreover, we determined the relationship between enzymatic AG degradation in rat liver microsomes and IDT risk.
酰基葡萄糖醛酸苷（AGs）被认为会导致药物特异质毒性（IDT），评估 AG 的化学不稳定性可能有助于预测新型候选药物的 IDT 风险。然而，AG 表现出化学不稳定性、形成程度和酶水解的变化。因此，我们评估了肝微粒体中 AG 的形成程度、酶水解和化学不稳定性及其与 IDT 风险的关系。非甾体抗炎药（NSAIDs）根据其作为母体药物的 IDT 风险分为三类：安全（SA）、警告（WA）和撤市（WDN）。为了评估 AG 的酶促和非酶促降解，将母体药物与大鼠肝微粒体在不存在或存在 AG 水解酶抑制剂的情况下孵育。AG 的形成和消失程度被认为是速率常数。对于所有研究的 NSAIDs，在添加 AG 水解酶抑制剂后，形成的 AG 数量明显增加。特别是，在不存在 AG 水解酶抑制剂的情况下，WDN 药物产生的 AG 水平低于 WA 和 SA 药物，但添加 AG 水解酶抑制剂后，AG 的产生显著增加。AG 形成和非酶促 AG 消失的速率常数在 WDN、WA 和 SA 药物之间没有显著差异，而 WDN 药物的酶促 AG 消失速率常数趋于高于 WA 和 SA 药物。总之，我们通过同时在肝微粒体中产生 AG 来评估 AG 的酶促降解和化学不稳定性。这种方法可以在不制备 AG 的情况下评估 AG 的降解。此外，我们确定了大鼠肝微粒体中酶促 AG 降解与 IDT 风险之间的关系。
