Dukaew Nahathai, Thongkumkoon Patcharawadee, Sirikaew Nutnicha, Dissook Sivamoke, Sakuludomkan Wannachai, Tongjai Siripong, Thiennimitr Parameth, Na Takuathung Mingkwan, Benjanuwattra Juthipong, Kongthaweelert Prachya, Koonrungsesomboon Nut
Department of Pharmacology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Road, Sriphoom, Muang, Chiang Mai 50200, Thailand.
Clinical Research Center for Food and Herbal Product Trials and Development (CR-FAH), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Pharmaceutics. 2023 Jun 14;15(6):1734. doi: 10.3390/pharmaceutics15061734.
Mycophenolic acid (MPA) and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed together in certain groups of patients, including solid organ transplant recipients. However, little is known about the pharmacokinetic drug-drug interactions (DDIs) between these two medications. Therefore, the present study aimed to determine the effects of TMP-SMX on MPA pharmacokinetics in humans and to find out the relationship between MPA pharmacokinetics and gut microbiota alteration. This study enrolled 16 healthy volunteers to take a single oral dose of 1000 mg mycophenolate mofetil (MMF), a prodrug of MPA, administered without and with concurrent use of TMP-SMX (320/1600 mg/day) for five days. The pharmacokinetic parameters of MPA and its glucuronide (MPAG) were measured using high-performance liquid chromatography. The composition of gut microbiota in stool samples was profiled using a 16S rRNA metagenomic sequencing technique during pre- and post-TMP-SMX treatment. Relative abundance, bacterial co-occurrence networks, and correlations between bacterial abundance and pharmacokinetic parameters were investigated. The results showed a significant decrease in systemic MPA exposure when TMP-SMX was coadministered with MMF. Analysis of the gut microbiome revealed altered relative abundance of two enriched genera, namely the genus and , following TMP-SMX treatment. The relative abundance of the genera , group, group, and appeared to be significantly correlated with systemic MPA exposure. Coadministration of TMP-SMX with MMF resulted in a reduction in systemic MPA exposure. The pharmacokinetic DDIs between these two drugs were attributed to the effect of TMP-SMX, a broad-spectrum antibiotic, on gut microbiota-mediated MPA metabolism.
霉酚酸（MPA）和甲氧苄啶-磺胺甲恶唑（TMP-SMX）通常在某些患者群体中联合使用，包括实体器官移植受者。然而，关于这两种药物之间的药代动力学药物-药物相互作用（DDIs）知之甚少。因此，本研究旨在确定TMP-SMX对人体MPA药代动力学的影响，并找出MPA药代动力学与肠道微生物群变化之间的关系。本研究招募了16名健康志愿者，单次口服1000mg霉酚酸酯（MMF），MMF是MPA的前体药物，在不使用和同时使用TMP-SMX（320/1600mg/天）的情况下给药5天。使用高效液相色谱法测量MPA及其葡糖醛酸化物（MPAG）的药代动力学参数。在TMP-SMX治疗前后，使用16S rRNA宏基因组测序技术对粪便样本中的肠道微生物群组成进行分析。研究了相对丰度、细菌共现网络以及细菌丰度与药代动力学参数之间的相关性。结果表明，当TMP-SMX与MMF联合使用时，全身MPA暴露量显著降低。肠道微生物组分析显示，TMP-SMX治疗后，两个富集菌属，即属 和 ，的相对丰度发生了变化。属 、 组、 组和 的相对丰度似乎与全身MPA暴露量显著相关。TMP-SMX与MMF联合给药导致全身MPA暴露量降低。这两种药物之间的药代动力学DDIs归因于广谱抗生素TMP-SMX对肠道微生物群介导的MPA代谢的影响。
