Metabolite patterns of the carbonic anhydrase inhibitors brinzolamide and dorzolamide: potential markers for the route of application
Bibliographic record
Abstract
Brinzolamide (BA) and dorzolamide (DA) are carbonic anhydrase inhibitors (CAIs), and are commonly used therapeutics for glaucoma treatment via topical application. According to the regulations of the World Anti-Doping Agency (WADA), both drugs are classified under "Diuretics and Masking Agents", prohibiting their use in- and out-of-competition, except for ophthalmic application. Despite ophthalmic use being permitted, systemic absorption occurs, enabling BA and DA detection in blood and urine samples after topical administration. Thus, distinguishing between legitimate (e.g. topical) and prohibited (e.g. oral) drug application routes is critical for sports drug testing result management. This study investigated the elimination and metabolic profiles of BA and DA following topical and systemic administration in male piglets. Three piglets received BA or DA ophthalmic suspensions, while another three received an oral dose. Urine and blood samples were collected over one week, and all samples were analysed using liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS MS). In vitro experiments yielded five phase I metabolites for DA and BA. After method validation, the approach was confirmed to detect DA and BA, with Limits of Detection (LODs) of 55 pg/mL and 75 pg/mL in urine, 110 pg/mL and 180 pg/mL in red blood cells, and 380 pg/mL and 910 pg/mL in plasma. BA and DA metabolites were primarily found in the red blood cell fraction, with only trace amounts detectable in plasma. N-desethylation was observed as the main metabolic reaction for both drugs, and metabolite-to-parent drug ratios were determined in all collected post-administration samples alongside drug concentration levels. The combined consideration of analyte ratios and drug concentrations appears to be indicative of time and dose of drug use (under the chosen routes of administration), which might assist in sports drug testing result management.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".