Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Laboratory of Quality & Safety Risk Assessment for Animal Products on Chemical Hazards (Beijing), Ministry of Agriculture and Rural Affairs of the People's Republic of China, Beijing 100193, China.
Molecules. 2023 Oct 20;28(20):7193. doi: 10.3390/molecules28207193.
Lekethromycin (LKMS) is a synthetic macrolide compound derivative intended for use as a veterinary medicine. Since there have been no in vitro studies evaluating its potential for drug-drug interactions related to cytochrome P450 (CYP450) enzymes, the effect of the inhibitory mechanisms of LKMS on CYP450 enzymes is still unclear. Thus, this study aimed to evaluate the inhibitory effects of LKMS on dog CYP450 enzymes. A cocktail approach using ultra-performance liquid chromatography-tandem mass spectrometry was conducted to investigate the inhibitory effect of LKMS on canine CYP450 enzymes. Typical probe substrates of phenacetin, coumarin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and testosterone were used for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4, respectively. This study showed that LKMS might not be a time-dependent inhibitor. LKMS inhibited CYP2A6, CYP2B6, and CYP2D6 via mixed inhibition. LKMS exhibited mixed-type inhibition against the activity of CYP2A6 with an inhibition constant (K) value of 135.6 μΜ. LKMS inhibited CYP2B6 in a mixed way, with K values of 59.44 μM. A phenotyping study based on an inhibition assay indicated that CYP2D6 contributes to the biotransformation of LKMS. A mixed inhibition of CYP2D6 with K values of 64.87 μM was also observed. Given that this study was performed in vitro, further in vivo studies should be conducted to identify the interaction between LKMS and canine CYP450 enzymes to provide data support for the clinical application of LKMS and the avoidance of adverse interactions between other drugs.
来立信（LKMS）是一种合成的大环内酯类化合物衍生物，拟用于兽医。由于没有体外研究评估其对细胞色素 P450（CYP450）酶相关药物-药物相互作用的潜力，因此 LKMS 对 CYP450 酶的抑制机制的影响仍不清楚。因此，本研究旨在评估 LKMS 对犬 CYP450 酶的抑制作用。采用超高效液相色谱-串联质谱的鸡尾酒方法研究 LKMS 对犬 CYP450 酶的抑制作用。使用苯乙酮、香豆素、丁普隆、甲苯磺丁脲、右美沙芬、氯唑沙宗和睾酮的典型探针底物分别用于 CYP1A2、CYP2A6、CYP2B6、CYP2C9、CYP2D6、CYP2E1 和 CYP3A4。本研究表明，LKMS 可能不是时间依赖性抑制剂。LKMS 通过混合抑制抑制 CYP2A6、CYP2B6 和 CYP2D6。LKMS 对 CYP2A6 的活性表现出混合抑制作用，抑制常数（K）值为 135.6 μM。LKMS 以混合方式抑制 CYP2B6，K 值为 59.44 μM。基于抑制试验的表型研究表明 CYP2D6 有助于 LKMS 的生物转化。还观察到 K 值为 64.87 μM 的 CYP2D6 混合抑制。鉴于本研究是在体外进行的，应进行进一步的体内研究以确定 LKMS 与犬 CYP450 酶之间的相互作用，为 LKMS 的临床应用和避免其他药物之间的不良相互作用提供数据支持。
