Effects of inflammation on a model of cytochrome P450 dependent versus independent antihypertensives: losartan versus valsartan
Bibliographic record
Abstract
Previous studies have demonstrated that the pharmacokinetics of cytochrome P450 (CYP450) metabolized drugs may be altered in inflammation. The objective of this study was to determine whether the pharmacokinetics and associated pharmacodynamics of a CYP450-activated drug (losartan) would be affected by inflammation when compared to a non-CYP450 metabolized drug (valsartan). Fourteen patients with acute rheumatoid arthritis, 12 patients with rheumatoid arthritis in remission and 8 healthy controls took part in this study. Losartan 100 mg or valsartan 160 mg were administered as a single oral dose in a double-blind, randomized order to study subjects. At specified intervals after dosing, blood was sampled for measurement of valsartan, losartan and losartan active metabolite, EXP3174, levels. Pharmacodynamic measurements were carried out at the same time as pharmacokinetic measurements using an HDI Pulsewave monitor. Results were assessed based on clinical categorization as well as continuously based on inflammatory mediator levels. When assessed by clinical status, conversion of losartan to EXP3174 was inhibited in the acute and remittive rheumatoid arthritic patients compared to healthy controls (p=.024 for AUC EXP3174 and p=.037 for Cmax EXP3174, by ANOVA). Pharmacokinetics of valsartan were not significantly different between clinical groups (p=.92 by ANOVA). When assessed continuously based on baseline C-reactive protein level (CRP), the AUC ratio for EXP3174:losartan was inversely related to CRP(r=-.49, p=.004). Similar correlations were seen when tender swollen joints or total serum nitrites were used as dependent variables. In terms of pharmacodynamics, the Cmax of EXP3174 and the Cmax ratio of EXP3174:losartan correlated with maximum changes in mean arterial pressure and with area under the effect curves for mean arterial pressure and a number of other clinical variables. In multiple regression models, Cmax of EXP3174 was the strongest predictor of clinical effect for losartan. No pharmacodynamic differences were seen for valsartan when analyzed categorically by clinical status or continuously by various inflammatory markers. We conclude that in the presence of inflammation the activation or metabolism of CYP450-dependent angiotensin II receptor blockers such as losartan may be altered leading to changes in pharmacokinetics and hence, clinical effect. Non-CYP450 dependent ARBs such as valsartan seem to be unaffected by inflammation.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.002 | 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".