Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry, Hongkou, Shanghai 200437, PR China.
Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry, Hongkou, Shanghai 200437, PR China; School of Pharmacy, Fudan University, Pudong, Shanghai 201203, PR China.
Eur J Pharm Sci. 2022 Aug 1;175:106235. doi: 10.1016/j.ejps.2022.106235. Epub 2022 Jun 11.
Olsalazine is a typical 5-aminosalicylic acid (5-ASA) drug that depends on gut microbiota to liberate its anti-inflammatory moiety 5-ASA in the treatment of ulcerative colitis (UC). In recent decades, 5-ASA drugs combined with probiotics have achieved a better effective treatment for UC. Mechanisms of combination therapy have been widely discussed from a pharmacodynamic perspective. However, it is still unclear whether the better therapeutic efficacy of combination therapy was made by changing the metabolism of 5-ASA drugs in the colon under the regulation of probiotics. In the present study, combined with pharmacokinetic and gut microbiota analyses, we systematically evaluated the potential effect of Lactobacillus acidophilus (L. acidophilus) on the metabolism of Olsalazine at three levels (pharmacokinetic characteristics, metabolic microbiota, and metabolic enzymes) to offer some insights into this issue. As pharmacokinetic results showed, L. acidophilus barely had an influence on the pharmacokinetic parameters of Olsalazine, 5-ASA, and N-Ac-5-ASA. Notably, the colonic exposure of 5-ASA was not affected by L. acidophilus. Gut microbiota results also illustrated that L. acidophilus did not change the total abundance of azoreductase (azoR) and N-acetyltransferase (NAT) associated gut microbiota and enzymes, which are involved in the metabolism of Olsalazine. Both pharmacokinetic and gut microbiota results revealed that L. acidophilus did not increase the colonic exposure of 5-ASA to improve the efficacy of combination therapy. L. acidophilus played its role in UC treatment by regulating gut microbiota composition and amino acid, phenolic acid, oligosaccharide, and peptidoglycan metabolic pathways. There was no potential medication risk of combination therapy of Olsalazine and L. acidophilus. In summary, this research provided strong evidence of medication safety and a comprehensive understanding of therapeutic advantages for combination therapy of probiotics and 5-ASA drugs from the pharmacokinetic and gut microbiota perspectives.
奥沙拉嗪是一种典型的 5-氨基水杨酸（5-ASA）药物，在治疗溃疡性结肠炎（UC）时依赖肠道微生物群释放其抗炎部分 5-ASA。近几十年来，5-ASA 药物与益生菌联合使用已实现了对 UC 的更好的有效治疗。从药效学的角度广泛讨论了联合治疗的机制。然而，尚不清楚联合治疗的更好治疗效果是否是通过益生菌调节下改变结肠中 5-ASA 药物的代谢而产生的。在本研究中，我们结合药代动力学和肠道微生物组分析，系统地评估了嗜酸乳杆菌（Lactobacillus acidophilus，L. acidophilus）对奥沙拉嗪代谢的潜在影响，从三个水平（药代动力学特征、代谢微生物群和代谢酶）评估了其对奥沙拉嗪代谢的潜在影响，为解决这一问题提供了一些见解。药代动力学结果表明，L. acidophilus 几乎不影响奥沙拉嗪、5-ASA 和 N-Ac-5-ASA 的药代动力学参数。值得注意的是，L. acidophilus 并没有影响 5-ASA 的结肠暴露。肠道微生物组结果也表明，L. acidophilus 并没有改变参与奥沙拉嗪代谢的偶氮还原酶（azoR）和 N-乙酰基转移酶（NAT）相关肠道微生物群和酶的总丰度。药代动力学和肠道微生物组结果均表明，L. acidophilus 并没有增加 5-ASA 的结肠暴露，从而提高联合治疗的疗效。L. acidophilus 通过调节肠道微生物组组成和氨基酸、酚酸、寡糖和肽聚糖代谢途径发挥其在 UC 治疗中的作用。奥沙拉嗪和嗜酸乳杆菌联合治疗没有潜在的药物风险。总之，本研究从药代动力学和肠道微生物组的角度为益生菌和 5-ASA 药物联合治疗的药物安全性提供了有力证据，并对联合治疗的治疗优势有了全面的认识。
