Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. In Vitro Metabolism Studies
2.3. Competitive Inhibition Metabolism Assays
2.4. Analyte Quantitation
2.5. Data Analysis
2.6. PBPK Interaction Model
3. Results
3.1. In Vitro Metabolism
3.2. Interaction PBPK Modeling
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Compound | CAS | Molecular Weight | Molar Ratio | Molar Fraction | Carcinogenic A |
---|---|---|---|---|---|
(g/mol) | |||||
benzo(a)anthracene | 56-55-3 | 228.29 | 2.47 | 0.05 | EPA, IARC, ACGIH |
retene | 483-65-8 | 234.34 | 7.43 | 0.15 | |
pyrene | 129-00-0 | 202.25 | 14.50 | 0.28 | |
phenanthrene | 85-01-8 | 178.23 | 1.72 | 0.03 | |
naphthalene | 91-20-3 | 128.17 | 3.48 | 0.07 | EPA, IARC, ACGIH |
fluorene | 86-73-7 | 166.22 | 1.84 | 0.04 | |
fluoranthene | 206-44-0 | 202.25 | 14.24 | 0.28 | |
chrysene | 218-01-9 | 228.29 | 2.59 | 0.05 | EPA, ACGIH |
acenaphthylene | 208-96-8 | 154.21 | 2.00 | 0.04 | |
2-methylnaphthalene | 91-57-6 | 142.20 | 1.00 | 0.02 |
Model | BIC | |
---|---|---|
BaP | DBC | |
Michaelis-Menten | –71.1 | –71.6 |
Michaelis-Menten-clearance | –73.5 | –88.3 |
Double Michaelis-Menten | –71.5 | –86.8 |
Compound | Parameter | |||||||
---|---|---|---|---|---|---|---|---|
Vmax1 | Km1 | Clint1 | Clint2 | |||||
nmol/min/mg Micro | 95% CI | µM | 95% CI | mL/min | 95% CI | mL/min | 95% CI | |
BaP | 0.0063 | 0.0044–0.0083 | 0.088 | 0.044–0.15 | 0.072 | 0.054–0.10 | 0.0012 | 1.7 × 10−7–0.0028 |
DBC | 0.00090 | 0.00044–0.0023 | 0.060 | 0.014–0.22 | 0.015 | 0.0097–0.032 | 0.0017 | 6.5 × 10−7–0.0028 |
Substrate | Inhibitor | |||||
---|---|---|---|---|---|---|
KiBaP | KiDBC | KiSM10 | ||||
µM | 95% CI | µM | 95% CI | µM | 95% CI | |
BaP | 0.44 | 0.36–0.54 | 0.75 | 0.49–1.1 | ||
DBC | 0.061 | 0.041–0.12 | 0.63 | 0.36–1.2 |
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Smith, J.N.; Gaither, K.A.; Pande, P. Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling. Int. J. Environ. Res. Public Health 2022, 19, 8266. https://doi.org/10.3390/ijerph19148266
Smith JN, Gaither KA, Pande P. Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling. International Journal of Environmental Research and Public Health. 2022; 19(14):8266. https://doi.org/10.3390/ijerph19148266
Chicago/Turabian StyleSmith, Jordan N., Kari A. Gaither, and Paritosh Pande. 2022. "Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling" International Journal of Environmental Research and Public Health 19, no. 14: 8266. https://doi.org/10.3390/ijerph19148266