RESUMEN
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 Bacteroides and Faecalibacterium, following TMP-SMX treatment. The relative abundance of the genera Bacteroides, [Eubacterium] coprostanoligenes group, [Eubacterium] eligens group, and Ruminococcus 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.
RESUMEN
BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis. However, there has been no cost-effective tool for the investigation of the severity and progression of the disease because using OA standard diagnostic methods causes cartilage damage. OBJECTIVE: To evaluate the relationship between serum chondroitinsulphate WF6 (CS-WF6) and hyaluronate (HA) and the severity of knee OA according to Kellgren-Lawrence (K/L) grades of radiographic severity and minimal joint space width (JSWV). MATERIAL AND METHOD: One-hundred and twenty-six patients with OA (knee) according to K/L grades were classified into four groups. The JSW of the tibiofemoraljoint were measured from standing PA radiographs. Serum CS-WF6 and HA were analyzed by the ELISA based technique. One-way analysis of variance, Bonferroni's method and Kendall's tau coefficient relation test were performed to evaluate the association of K/L grades and JSW with levels of CS-WF6 and HA, respectively. RESULTS: Serum CS-WF6 levels in grade 4 were significantly increased when compared with the other grades (p < 0.05). The serum HA level did not show any significant difference among the grades of severity. The serum CS-WF6 level showed a significant negative correlation with the JSW and its levels rose rapidly to the level beyond 300 ng/ml. There was no correlation found between the levels of serum HA and JSW CONCLUSION: WF6 levels may be useful in identifying patients at risk of rapid progression reflected by a point of an abruptly high WF6 level. The determination of WF6 in the serum showed increasing levels in more severe grades, so it could be useful in monitoring the effectiveness of treatment. There were some limitations because of broad distribution and overlap with the normal range. Thus, it may not be suitable as a diagnostic tool.
