Abstract 4406: Multiple organic anion transporting polypeptides (OATPs) contribute to the in vitro and in vivo disposition of docetaxel
Bibliographic record
Abstract
Abstract Docetaxel is one of the most widely used antineoplastic agents and is approved for the treatment of breast, lung, ovarian, prostate, gastric, and head and neck cancers. It is a semisynthetic taxane derived from an extract of the needles of European yew tree (Taxus baccata). Docetaxel promotes the assembly of microtubules and stabilizes their formation by inhibiting depolymerization and cell death results from inhibition of normal microtubule processes. While it is known that docetaxel is a substrate of efflux transporters such as P-glycoprotein (P-gp), less is known regarding transporters that could mediate its cellular uptake. Accordingly, an array of drug uptake transporters, including organic anion, organic cation and bile acid transporters, were evaluated for radiolabeled docetaxel transport utilizing a recombinant vaccinia-based method in a heterologous cell system. Screening transport experiments and kinetic analysis in HeLa cells demonstrated that multiple organic anion transporting polypeptides (OATPs), including OATP1A2, OATP1B1, and OATP1B3, were capable of docetaxel transport in vitro. In addition, after intravenous administration, in vivo docetaxel transport experiments in Oatp1b2-/- mice (ortholog to hepatic OATP1B1/OATP1B3) revealed ∼5-fold higher plasma concentrations of docetaxel in Oatp1b2-/- mice versus their wild-type counterparts. The liver to plasma ratio of docetaxel was ∼3-fold increased in wild-type mice versus Oatp1b2-/- mice. Furthermore, the pharmacokinetic profile of docetaxel is characterized by substantial interindividual variability, with an up to tenfold difference in drug clearance, even in patients with normal hepatic function. A panel of single nucleotide polymorphisms (SNPs) in OATPs was assessed for docetaxel transport. Multiple SNPs in SLCO1A2, 1B1 and 1B3 were associated with impaired docetaxel transport in vitro. In conclusion, multiple OATPs were capable of transporting docetaxel in vitro and in vivo, suggesting these transporters are important to docetaxel disposition. A number of OATP variants were associated with significantly impaired docetaxel transport, which may have important toxicological and therapeutic ramifications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4406. doi:10.1158/1538-7445.AM2011-4406
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 0.001 |
| 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".