Impact of Inflammation on the Expression of Renal Drug Transporters
Bibliographic record
Abstract
Inflammation-mediated changes in the expression and activity of drug transporters and drug metabolizing enzymes have been shown to alter disposition of their substrates. Renal drug transporters including ABC and SLC transporters play an important role in the clearance of several drug substrates, as well as numerous endogenous compounds. Little is known about the impact of inflammatory stimuli on renal transporters. Using rodent models, we investigated the impact of inflammation on the expression of clinically important renal drug transporters. Three inflammatory conditions were examined as part of this thesis: inflammation elicited by HIV viral proteins, by bacterial endotoxin, and by the viral mimetic poly I:C. In a series of in vivo studies, endotoxin was administered to male HIV1-Transgenic (HIV1-Tg) and wild type (WT) rats to model the presence of endotoxemia in HIV patients. Endotoxin administration significantly downregulated numerous renal drug transporters in both HIV1-Tg and WT rats 18 h after administration. In addition, the presence of the HIV transgene alone in the absence of endotoxin resulted in the downregulation of the mRNA expression of several drug transporters. Although HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters, co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates and could potentially be a source of drug-disease interactions. In the next set of in vivo studies, poly I:C or saline was administered to pregnant rats at term. Poly I:C imposed a significant reduction in the mRNA and protein expression of numerous renal drug transporters 24 h after administration. Next, poly I:C or saline was administered to pregnant rats at mid-gestation and the impact of poly I:C was investigated at different time points. The mRNA expression of several drug transporters was downregulated at 6 h, and corresponding alterations at the protein level occurred at 48 h. Overall, poly I:C imposed significant reductions in the expression of several key renal transporters at term and mid-gestation in pregnant rats. Thus, viral infection may impact renal excretion of drug transporter substrates, potentially leading to drug–disease interactions.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".