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Printable Handouts
Navigable Slide Index
- Introduction
- Acknowledgements - Robert A. Branch
- Outline
- Drug metabolizing enzymes in the liver
- Evidence of change
- Extent of change in an individual patient
- Antipyrine half-lives, normal / in liver disease
- Can a quantitative liver function be developed?
- Child-Pugh score
- The Child-Pugh score: limitations
- Drug metabolism as a marker of liver disease
- Questions this talk will answer
- Pathophysiology of liver disease
- Hepatic acinar unit: basis for liver disease
- Pathophysiology of liver disease/cirrhosis
- Pathophysiology of liver disease/cirrhosis (2)
- Liver disease
- Physiological determinants of hepatic elimination
- Determinants of hepatic clearance
- High intrinsic clearance drug
- Low intrinsic clearance drug
- Effect of liver disease on elimination of a drug
- Single oral dosing
- Metabolism of Mephenytoin
- Loss of first pass presystemic elimination
- Intact hepatocyte theory
- Proposed theories for metabolism impairment
- Intact hepatocyte theory (2)
- Enzyme-limited and flow-limited drugs
- Intact nephron
- Intact nephron hypothesis
- Intact hepatocyte hypothesis
- Implications
- Prediction of modification of drug clearance
- Effect on alternative routes of metabolism
- Differential effect on oxidative metabolism
- Influence on oxidation vs. conjugation of drugs
- Chronic liver disease and clearance of morphine
- Several probe drugs in the same cohort
- Probe drugs
- Regulation of CYPs and disease severity
- Selective regulation of CYPs in chronic disease
- Liver transplantation
- Progressive sequential effect model
- Applications
- Extended Pittsburgh cocktail
- Effect over time and disease prognosis
- Follow up using a cocktail of probe drugs
- Specific disease entities
- Cholestatic disease vs. other
- Use of a cocktail of probe drugs in cirrhosis
- Use of a cocktail of probe drugs in cirrhosis (2)
- Hepatic steatosis
- Gene expression
- PBMCs mRNA as a marker for enzyme activity
- Coordinated regulation
- Epigenetic mechanisms
- Epigenetic changes leading to drug response
- Current knowledge - genes epigenetic regulation
- DNA methylation dynamics - CYP3A4 gene
- Functionally relevant differences in methylation
- Heat map of correlation analysis
- Univariate analysis of nongenetic factors
- Role of miRNA in fatty liver disease
- Peripheral DNA methylation & circulating miRNA
- Questions and answers
- Summary
Topics Covered
- Drug metabolism
- Liver disease and drug clearance
- Mechanistic explanations
- Intact hepatocyte hypothesis
- Sequential progressive model of liver disease
- Liver disease etiology
- Liver disease severity
- Epigenetics
- Biomarkers
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Zgheib, N. and Branch, R. (2020, August 12). Drug metabolism in liver disease [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/IVAV2934.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Nathalie Zgheib has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
- Prof. Robert Branch has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Metabolism & Nutrition
Transcript
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0:00
The talk is about drug
metabolism in liver disease.
I am an associate professor
in pharmacology and toxicology
at the American
University of Beirut.
Please feel free to email
me if you have any question.
0:14
I'd like to acknowledge
Dr. Robert Branch
from the University of Pittsburgh.
He's my mentor.
A lot of the studies
that I will mention today
were conducted by his group.
He has given the
original talk in 2007.
0:29
Here's the outline
that I will follow.
I will first start with a
little bit of background
on drug metabolism in liver disease.
Is there any evidence of change?
And is this clinically relevant?
This is very important
for physicians
who prescribe those drugs in
the setting of liver disease.
Then, we will talk
about pathophysiology
of liver disease and physiology
of hepatic elimination.
And with this
background, then you will
be able to understand
better the effect of
liver disease on drug metabolism.
We will talk about the
intact hepatocyte theory.
And then move on to the progressive,
sequential model in liver disease.
And after that, we will see
some applications of this model
in liver disease over
time and whether it
has a role in disease prognosis.
We will look at different
disease entities,
such as cholestatic liver disease
versus non-cholestatic
liver disease.
And towards the end, we will
try to see if gene expression
or epigenetic mechanisms such as
DNA methylation and miRNA expression
can be used as biomarkers of
drug metabolism in liver disease.
1:38
We all know that drug
metabolizing enzymes
are concentrated in the liver.
Hence, it would make sense that
most probably liver disease affects
their expression and activity.