Summary

Summary Preclinical drug research: In vitro metabolism assessment techniques

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Course
Preclinical drug reserach (2031FBDBMW_2324)

Institution
Universiteit Antwerpen (UA)

In vitro metabolism assessment techniques (isolation, advantages, disadvantages): - liver microsomes - S9 fraction - primary hepatocytes - liver slices - recombinant enzymes - permanent cell lines

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Uploaded on January 20, 2024
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Written in 2023/2024
Type Summary

permanent cell lines
recombinant enzymes
liver slices
primary hepatocytes
s9 fraction
liver microsomes
metabolism
metabolism assessment
safety pharmacokinetics

Institution
Universiteit Antwerpen (UA)
Education
Biomedische Wetenschappen
Course
Preclinical drug reserach (2031FBDBMW_2324)

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Methods to assess in vitro metabolism:

- Liver microsomes: They are obtained via ultracentrifugation (pellet) and solved in buffer with
go-factors, the drug compound, and to assess UDT affinity: a second compound is added.
The fraction contains phase I enzymes (especially CYPs- and UDT (UDP-
glucuronysyltransferase, a phase II enzyme).
The affinity for phase I enzymes can be assessed, also the affinity to UDT can be assessed by
adding a second compound.
Advantages:
+: easy to obtain
+: CYPS are completely concentrated (pure) so focus on phase I
+: inhibition studies possible  add inhibitor
Disadvantages:
-: specific substrates and inhibitors required
-: contains only phase I enzymes and UGT
-: no induction studies possible
- S9 fraction: Obtained via centrifugation at 9000xg (supernatant).
The fraction contains both phase I and phase II enzymes, but less pure than liver microsomes.
Advantages:
+: more complete view (because both phase I and phase II enzymes present)
+: inhibition studies possible
Disadvantages:
-: no induction studies possible
- Primary hepatocytes: contain the complete cell (whole cell ‘machinery’); contain all enzymes.
Advantages:
+: contain whole cell ‘machinery’: induction studies possible
+: contain all metabolizing enzymes so higher metabolizing capacity qualitative
metabolizing profile
Disadvantages:
-: difficult to obtain
-: requires specific techniques
-: metabolizing capacity of DME’s (drug metabolizing enzymes) decreases rapidly after
cultivation
-: takes more time
- Liver slices: liver slices with all cells present.
Advantages:
+: resemble most closely to the in vivo situation
Disadvantages:
-: difficult to obtain: fresh samples  practically not possible
-: levels of DMEs decrease rapidly after cultivation
-: requires specific techniques
- Recombinant enzymes: CYP or UGT: individual enzymes are produced in ER of host cell by
gene expression.
Advantages:
+: affinity for specific enzymes can be assessed like CYP3A4, if high affinity  dose should be
increased
Disadvantages:
-: only 1 enzyme at a time

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