The pharmacokinetics and pharmacodynamics of 4-methylumbelliferone and its glucuronide metabolite in mice
Bibliographic record
Abstract
Abstract Hyaluronan (HA) is an extracellular matrix glycosaminoglycan, with important roles in chronic inflammation, cancer and autoimmunity. 4-methylumbelliferone (4-MU), a small molecule inhibitor of HA synthases, is widely used to study HAs interactions with the surrounding tissues and the immune cells. There is substantial experimental and therapeutic interest in using oral 4-MU to inhibit HA synthesis, but pharmacokinetic and pharmacodynamic data on treatment routes have been lacking. Moreover, it recently became clear that the main metabolite of 4-MU, 4-methlyumbelliferyl glucuronide (4-MUG), is bioactive. We therefore sought to define the pharmacokinetics and pharmacodynamics of 4-MU and its active metabolite 4-MUG in mice. Single dose mouse studies showed that 4-MU administered intravenously (i.v.) resulted in 100-fold higher 4-MU exposure compared to oral (p.o.) administration. The 4-MU ratio AUC i.v./AUC p.o. was 96/1. 4-MUG exposures were much higher than 4-MU exposures after both 4-MU i.v. and p.o. administration, but only small differences in 4-MUG exposure were seen after 4-MU i.v. versus p.o. administration. The 4-MUG metabolite was also administered as a single dose both i.v. and p.o. and showed a 25.9% bioavailability. Compared to 4-MUG p.o. dosing, 1.14 higher 4-MUG exposures were seen after 4-MU p.o. dosing. 4-MU exposure after 4-MUG p.o. administration was minimal but similar to 4-MU exposure after 4-MU p.o. administration. In mice treated for several weeks with 4-MU in chow, the 4-MU concentration immediately drops after treatment was stopped, whereas the 4-MUG concentration showed a peak 1 hour after treatment stop. In a build-up study, 4-MU and 4-MUG treatment in mice lead to a plateau of 4-MU concentration starting at 4 days post treatment start. These 4-MU and 4-MUG concentration findings in vivo will inform future clinical studies and experimental work with 4-MU.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".