Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework
Abstract
:1. Introduction
2. Materials and Methods
2.1. Establishing 4β-OHC Baseline Plasma Concentrations across Populations by Meta-Analysis
2.2. PBPK Model Development
2.2.1. Distribution
2.2.2. Elimination
- Step 1: Calculation of CYP450-Specific Intrinsic Clearance of Cholesterol
- Step 2: Optimization of Fraction Metabolized by CYP3A ()
2.2.3. Trial Design
2.3. PBPK Model Performance and Verification
2.4. Statistical Assessment of Model Prediction Accuracy
2.5. PBPK Model Application
2.5.1. CYP3A4 Polymorphism
2.5.2. CYP3A5 Polymorphism
2.5.3. RA Patients
2.5.4. Effect of Other CYP3A4 Inducers
2.6. Statistical Analysis of 4β-OHC Levels in Different Groups
3. Results
3.1. Ethnic and Sex-Specific Differences in Baseline 4β-OHC Levels
3.2. PBPK Model Development and Performance Verification
3.3. PBPK Model Applications
3.3.1. CYP3A4*22 Carriers Show Reduced CYP3A4 Protein Content and Baseline 4β-OHC Levels
3.3.2. The Impact of CYP3A5 Polymorphisms
3.3.3. Rheumatoid Arthritis (RA) Patients Exhibit Lower 4β-OHC Levels
3.3.4. DDI Simulation with Other CYP3A4 Inducers
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cholesterol | 4β-OHC | |||
---|---|---|---|---|
Parameter | Value | Source/Reference | Value | Source/Reference |
Physicochemical Parameters | ||||
Molecular weight (g/mol) | 386.65 | HMDB ID (HMDB0000067) | 402.35 | HMDB (HMDB0013643) |
log P | 7.02 | HMDB ID (HMDB0000067) | 6.16 | HMDB ID (HMDB0013643) |
Compound type | Neutral | Neutral | ||
Blood Binding Parameters | ||||
B/P | 0.55 | [18] | 0.55 | [18] |
fup | 0.0021 Predicted (QSAR) | [20] | 0.0051 Predicted (QSAR) | [20] |
Reference binding component | Apolipoprotein B | [21] | Apolipoprotein B | [21] |
Protein reference concentration (µM) | 620 | Optimized. Please see the methods Section 2.2 for details. | 620 | Optimized. Please see the methods Section 2.2 for details. |
Distribution | Minimal PBPK Model | |||
Vss (L/kg) | 0.10 | User input | 0.05 | User input |
Liver Kp | 3.07 | Calculated from [23]. See Table S1. | 3.87 | Calculated from [23]. See Table S1. |
Elimination | Enzyme Kinetics | |||
CYP3A4 CLint (µL/min/pmol) | 4.17 × 10−7 | Optimized. Please see the methods Section 2.2.2 for details. | N.A. | Optimized. Please see the methods Section 2.2.2 for details. |
CYP3A5 CLint (µL/min/pmol) | 2.55 × 10−8 | N.A. | ||
CYP3A7 CLint (µL/min/pmol) | 1.27 × 10−8 | N.A. | ||
CYP27A1 CLint (µL/min/pmol) | 3.13 × 10−3 | 0.02 | ||
Additional HLM CLint (μL/min/mg protein) | 0.350 | 0.84 |
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Karkhanis, A.V.; Harwood, M.D.; Stader, F.; Bois, F.Y.; Neuhoff, S. Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework. Pharmaceutics 2024, 16, 1284. https://doi.org/10.3390/pharmaceutics16101284
Karkhanis AV, Harwood MD, Stader F, Bois FY, Neuhoff S. Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework. Pharmaceutics. 2024; 16(10):1284. https://doi.org/10.3390/pharmaceutics16101284
Chicago/Turabian StyleKarkhanis, Aneesh V., Matthew D. Harwood, Felix Stader, Frederic Y. Bois, and Sibylle Neuhoff. 2024. "Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework" Pharmaceutics 16, no. 10: 1284. https://doi.org/10.3390/pharmaceutics16101284
APA StyleKarkhanis, A. V., Harwood, M. D., Stader, F., Bois, F. Y., & Neuhoff, S. (2024). Applications of the Cholesterol Metabolite, 4β-Hydroxycholesterol, as a Sensitive Endogenous Biomarker for Hepatic CYP3A Activity Evaluated within a PBPK Framework. Pharmaceutics, 16(10), 1284. https://doi.org/10.3390/pharmaceutics16101284