Study of Jadomycin Pharmacokinetics in Balb/C Mice
Bibliographic record
Abstract
Background Jadomycins are natural product molecules derived from the soil bacteria Streptomyces venezuelae ; jadomycins maintain their cytotoxicity in multidrug resistant (MDR) human and mouse breast cancer cell lines that overexpress ATP‐binding cassette (ABC) transporters. While effective in in vitro assays, jadomycins have not been studied in animal models. Objective To conduct the first in animal pharmacokinetic and safety studies of jadomycins B, S, and F in male and female Balb/C mice. Methods Jadomycins were administered intraperitoneally (IP) to male and female Balb/C mice at a 6mg/kg dose. In one group of mice (n = 5) up to four repeated saphenous vein blood samples (40 mL) were obtained after 15, 30, 60, and 90 minutes with terminal blood collection occurring at 120 minutes in order to characterize absorption and distribution phases. In a second group of mice saphenous vein blood samples were obtained at 2, 4, 6, 8 and 10 hours to characterize terminal elimination. Liver, kidney, lung and brains were collected after 2 hours and then at 8 or 10 hours (males and females respectively) to characterize jadomycin distribution to these tissues. Serum and tissue samples underwent extraction and jadomycin concentrations were then determined by mass spectrometry. Results The concentration versus time profiles of jadomycins B, S and F were similar. They were absorbed rapidly after IP injection with peak concentrations in the 1–10 mM range observed after 15 minutes. This was followed by a rapid distribution phase (t 1/2 a = 20 – 40 min) and a slower terminal elimination (t 1/2 b = 1.5 – 2 hours). Jadomycins accumulated in the liver > kidney > lung and were not detectable in the brain. No metabolites were detected and no acute toxicity responses were observed. Conclusions These 1 st in vivo studies of jadomycins reveal that jadomycins are safe at a 6 mg/kg IP dose and achieve concentrations in mouse serum that are above the IC50s (1–4 μM) for human and mouse breast cancer cells in vitro. Our results indicate that jadomycins are rapidly eliminated as unchanged drug and that two to three times daily dosing will be required for future tumor studies. Support or Funding Information Cancer Research Training Program (CRTP) through Beatrice Hunter Cancer Research Institute, Canadian Breast Cancer Foundation Atlantic (CBCF), Nova Scotia Health Research Foundation (NSHRF), and Dalhousie University
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".