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Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates
- Source :
- Pharmaceutical research. 38(3)
- Publication Year :
- 2021
-
Abstract
- For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP). The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.
- Subjects :
- Drug
Physiologically based pharmacokinetic modelling
Antifungal Agents
media_common.quotation_subject
Midazolam
Pharmaceutical Science
Inflammation
02 engineering and technology
CYP2C19
Pharmacology
030226 pharmacology & pharmacy
Models, Biological
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
medicine
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme Inhibitors
Humans
Pharmacology (medical)
Computer Simulation
Drug Interactions
media_common
CYP3A4
biology
Chemistry
Organic Chemistry
Cytochrome P450
021001 nanoscience & nanotechnology
In vitro
Cytochrome P-450 CYP2C19
biology.protein
Molecular Medicine
Voriconazole
medicine.symptom
0210 nano-technology
Omeprazole
Biotechnology
Subjects
Details
- ISSN :
- 1573904X
- Volume :
- 38
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Pharmaceutical research
- Accession number :
- edsair.doi.dedup.....30dd3d66707b87078f1343e4071c6242