# Pharmacometabolomics Study of Sulfamethoxazole and Trimethoprim in Kidney Transplant Recipients: Real-World Metabolism and Urinary Excretion

## TL;DR

This study examines how the antibiotic cotrimoxazole is metabolized and excreted in kidney transplant patients, revealing new metabolites and their potential environmental impact.

## Contribution

The study identifies previously unreported metabolites of cotrimoxazole and highlights their relevance for environmental and clinical monitoring.

## Key findings

- Glucuronide conjugates and isoxazole ring-opened variants of sulfamethoxazole were identified as new metabolites.
- Trimethoprim accounted for 75% of the total signal intensity, indicating its significant presence in excretion.
- The study provides insights into real-world metabolism of cotrimoxazole in kidney transplant recipients.

## Abstract

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring.