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Developing the minipig for use in pharmacokinetic modeling : determination of microsomal and cytosolic scaling factors and validation of NQO1/NQO2 metabolism Zimmer, Austin Alphonse
Abstract
The in vitro in vivo extrapolation (IVIVE) technique, paired with Physiologically Based Pharmacokinetic Modelling (PBPK), is an alternative to in vivo testing. IVIVE PBPK utilizes scaling factors (scalars) obtained from tissue to model in vitro data calculating whole-body clearance. The most relevant tissues are metabolic and generally consist of; the liver (MPPGL/CPPGL) kidney (MPPGK/CPPGK) and intestine (MPPGI/CPPGI). While rodents and canines are traditionally used in these studies, they do not always capitulate accurate human situations. A proposed animal model with superior anatomical and biochemical homology in comparison to humans is the minipig, but it has not gained wider use in part due to limited data and characterization underlying IVIVE PBPK, including scalars and some enzyme families such as NAD(P)H Quinone Oxidoreductases (NQO1, NQO2). Herein, MPPGL (24 ± 3 mg protein/g tissue), CPPGL (76 ± 17 mg protein/g tissue), MPPGK (13 ± 4 mg protein/g tissue), CPPGK (40 ± 6 mg protein/g tissue), MPPGI (2 ± 0.7 mg protein/g tissue) and CPPGI (9 ± 0.8mg protein/g tissue) scalars have been defined for the first time in the Yucatan minipig. The effect of repeated freezing/thawing was evaluated and caused protein content to fluctuate indicating best practice is to avoid repeat freeze/thawing. The NQO1 and NQO2 activities were quantified for the first time in the minipig and were comparable to human for NQO1 liver and intestinal tissues, and NQO2 in kidney and intestinal tissues. NQO1 in kidney tissue was found to be 16 fold higher in the minipig, and 0.5 fold lower for NQO2 in minipig liver tissue, indicating that care is needed if using minipigs as a metabolic model where NQO enzymes are a major path of metabolism. These findings better characterize the minipig for use in IVIVE-PBPK models, improving uses in pre-clinical therapeutic and toxicity studies.
Item Metadata
| Title |
Developing the minipig for use in pharmacokinetic modeling : determination of microsomal and cytosolic scaling factors and validation of NQO1/NQO2 metabolism
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| Creator | |
| Supervisor | |
| Publisher |
University of British Columbia
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| Date Issued |
2024
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| Description |
The in vitro in vivo extrapolation (IVIVE) technique, paired with Physiologically Based Pharmacokinetic Modelling (PBPK), is an alternative to in vivo testing. IVIVE PBPK utilizes scaling factors (scalars) obtained from tissue to model in vitro data calculating whole-body clearance. The most relevant tissues are metabolic and generally consist of; the liver (MPPGL/CPPGL) kidney (MPPGK/CPPGK) and intestine (MPPGI/CPPGI). While rodents and canines are traditionally used in these studies, they do not always capitulate accurate human situations. A proposed animal model with superior anatomical and biochemical homology in comparison to humans is the minipig, but it has not gained wider use in part due to limited data and characterization underlying IVIVE PBPK, including scalars and some enzyme families such as NAD(P)H Quinone Oxidoreductases (NQO1, NQO2). Herein, MPPGL (24 ± 3 mg protein/g tissue), CPPGL (76 ± 17 mg protein/g tissue), MPPGK (13 ± 4 mg protein/g tissue), CPPGK (40 ± 6 mg protein/g tissue), MPPGI (2 ± 0.7 mg protein/g tissue) and CPPGI (9 ± 0.8mg protein/g tissue) scalars have been defined for the first time in the Yucatan minipig. The effect of repeated freezing/thawing was evaluated and caused protein content to fluctuate indicating best practice is to avoid repeat freeze/thawing. The NQO1 and NQO2 activities were quantified for the first time in the minipig and were comparable to human for NQO1 liver and intestinal tissues, and NQO2 in kidney and intestinal tissues. NQO1 in kidney tissue was found to be 16 fold higher in the minipig, and 0.5 fold lower for NQO2 in minipig liver tissue, indicating that care is needed if using minipigs as a metabolic model where NQO enzymes are a major path of metabolism. These findings better characterize the minipig for use in IVIVE-PBPK models, improving uses in pre-clinical therapeutic and toxicity studies.
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| Genre | |
| Type | |
| Language |
eng
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| Date Available |
2024-09-03
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| Provider |
Vancouver : University of British Columbia Library
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| Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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| DOI |
10.14288/1.0445299
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| URI | |
| Degree | |
| Program | |
| Affiliation | |
| Degree Grantor |
University of British Columbia
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| Graduation Date |
2024-11
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| Campus | |
| Scholarly Level |
Graduate
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| Rights URI | |
| Aggregated Source Repository |
DSpace
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Attribution-NonCommercial-NoDerivatives 4.0 International