The effect of increased lipoprotein levels on the pharmacokinetics of ketoconazole enantiomers in the rat
Bibliographic record
Abstract
(±)-Ketoconazole (KTZ) is a chiral antifungal drug that inhibits cytochrome P450 (CYP)-mediated metabolism of other drugs. Because of its lipophilicity, KTZ pharmacokinetics might change in elevated plasma lipoprotein concentrations. To explore that, the stereoselective pharmacokinetics of KTZ were assessed in a rodent model of hyperlipidaemia (HL). Rats were given KTZ intravenously (i.v.) or orally. Serial blood samples were collected over 24 h for the iv dosed groups. After oral doses, plasma and liver specimens were obtained up to 6 h after dosing. All specimens were assayed using stereospecific assay. Orally and iv dosed rats showed no significant differences between normolipidemic and hyperlipidaemic area under the plasma concentrations vs. time curves or clearance (CL), of both KTZ enantiomers. In iv dosed rats, however, the volume of distribution (V(ss)) was significantly higher in HL for both enantiomers. The (+):(-) KTZ ratios of CL and V(ss) were also higher in hyperlipidaemic rats. After oral doses, the liver to plasma concentration ratios of (-)-KTZ (but not antipode) were significantly lower in HL. In conclusion, HL caused an increase in V(ss), and possibly decreased liver uptake of the more potent CYP-inhibiting (-) enantiomer.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.001 | 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".