Transcript Drug Induced Liver Disease

Author(s): Rebecca W. Van Dyke, M.D., 2012
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M2 GI Sequence
Drugs and the Liver
Rebecca W. Van Dyke, MD
Winter 2012
Learning Objectives
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At the end of this lecture the students should be able to:
1. Describe the barrier function of the liver (and gut) with respect to drugs and xenobiotics.
2. Describe the hepatic pathways for handling and disposing of
drugs and xenobiotics.
3. Describe the pathophysiologic basis for drug-drug interactions at the level
of cytochrome P450 (CYP) enzymes.
4. Predict drug-drug interactions based on knowledge of relevant
P450 enzymes and inhibitors/inducers.
5. Describe the principals of drug-induced liver disease and be able to give
some representative examples.
6. Describe how alcohol consumption and/or poor nutritional status may
enhance susceptibility to acetaminophen-induced liver injury.
7. Describe an approach to drug-induced liver disease.
8. Describe the potential consequences of liver disease on drug metabolism
and the clinical effect of medications.
Industry Relationship
Disclosures
Industry Supported Research and
Outside Relationships
• None
Drugs and the Liver
Liver Disease
Drugs
LIVER
Drug-Drug
Interactions
Drug Elimination
Drug Metabolites
(the good, the bad and the ugly)
Why Study Drugs and the Liver?
• Liver is a major biotransforming and
elimination organ
– Barrier and “Garbage Disposal”
• Drug-drug interactions occur in liver
– May increase toxicity or reduce effect
• Drugs cause liver damage
– Mechanism and can it be predicted?
• Liver disease in turn alters drug disposal
(remember renal disease and drug
excretion?)
Barriers to uptake
of potentially undesirable
chemicals/xenobiotics
(an eternal problem):
1. Gut mucosa
2. Liver
Barrier consists of multiple
steps.
Not all xenobiotics are affected
by each step.
Hepatic Clearance of Drugs
• Liver removal of drugs/xenobiotics from
blood is termed hepatic clearance (ClH)
• Hepatic clearance is actually a very complex
process due to many steps
• Can be simplified to three factors
– Liver blood flow
– Liver intrinsic clearance
– Fraction of drug not bound to albumin
Hepatic Clearance of Drugs
Q (fx unbound drug) (ClINT)
ClH =
Q + (fx unbound)(ClINT)
Q = liver blood flow
ClINT = rate of ability of liver to clear blood of
drug if blood flow not limiting
Hepatic Drug Clearance
• For High Extraction Drugs:
• Equation reduces to simple form:
• ClH = Q
Effect of Efficient Extraction by Hepatocytes in Series
Portal
Vein
Input
Hepatic
Vein
Output
100%
5%
High Extraction Drugs/
Xenobiotics/ Endogenous
Compounds
•
•
•
•
Nitroglycerine
Lidocaine
Propranolol
Bile Acids
High Extraction Drugs:
Drugs/xenobiotics rapidly
cleared in a single pass
through the liver.
Consequences can be
good or bad:
Oral administration of drugs/
xenobiotics is inefficient –
must administer IV/IM.
However, enterohepatic
circulation of bile acids is
efficient.
Hepatic Drug Clearance
• For Low Extraction Drugs:
• Equation reduces to simple form:
• ClH = fx unbound x ClINT
Effect of Low Extraction Efficiency by Hepatocytes in Series
Portal
Vein
Input
Hepatic
Vein
Output
100%
80%
Low Extraction Drugs/
Endogenous Compounds
•
•
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Diazepam
Phenytoin
Theophylline
Bilirubin
1. These drugs are efficiently absorbed when given orally.
2. Thus bioavailability of orally administered drugs is high.
3. Drug companies look for these types of products as pills
are easy to take.
Steps in Liver Biotransformation
and Elimination of Drugs - I
• Transport of drugs/xenobiotics from blood
– Liver has unique access to blood
– Versatile transporters in liver membrane
• Biotransformation in the liver
– Phase I (cytochromes P450)
– Phase II (conjugation)
Steps in Liver
Biotransformation and
Elimination of Drugs - II
• Biliary excretion
• Efflux to blood for eventual renal
excretion
Liver Biotransformation and
Elimination of Drugs - III
• These processes exist for endogenous
compounds, not just for drugs and
xenobiotics
Phase 1 and Phase 2 Biotransformation in Liver
OH
OH
Sugar
Glucuronyl
transferase
CYP
ER
O
ER
Phase 1
Phase 2
Oxidative
reactions
CYP-mediated
Conjugation to polar ligand
Glucuronyl transferases
Sulfotransferases
Glutathione-Stransferases
Phase 1: Biotransformation
• Direct modification of primary structure
• Cytochromes P450
– Oxidative reactions
– Add reactive/hydrophilic groups (-OH)
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Often rate-limiting, located in ER
May eliminate or generate toxic molecules
Account for many drug-drug interactions
HIGHLY VARIABLE (genetic polymorphisms,
inhibitable, inducible)
Anatomy of the
Cytochromes
P450, a.k.a. CYP
Fe
Contributions of Specific
P450s to Drug Metabolism
CYP3A4
CYP2E1
CYP2D6
CYP2C*
CYP2C*
CYP1A2
unknown
* multiple subfamily
members exist
CYPs: Role in breakdown of active drug
Genetic variations: Desipramine Kinetics Due
to Polymorphisms in CYP 2D6
fast Extensive
Metabolizer
slow Extensive
Metabolizer
(most common)
Poor
Metabolizer
log plasma
Desipramine
concentration
TIME since administration
Implications for other drugs metabolized by CYP2D6: ??? Codeine
Role: Production of an active drug:
Biotransformation of an inactive pro-drug) to an active drug
pro-drug
active drug
OH
Glucuronyl
transferase
CYP3A4
ER
ER
Phase 2: Conjugation
• Catalyze covalent binding of drugs to polar
ligands (“transferases”)
– glucuronic acid, sulfate, glutathione, amino acids
• Increase water solubility
• Enzymes generally in ER, some cytosolic
• Often follow Phase I biotransformation
reactions
– frequently use -OH or other group added by
CYPs
Conjugation of acetaminophen to UDP-glucuronic acid
NH-CO-CH3
NH-CO-CH3
UDP
+
Glucuronic acid
OH
CYP
ER
O
Glucuronic acid
UDP-glucuronyl
transferase
ER
Phase II Conjugation
• Endogenous examples:
– Conjugation of bilirubin to glucuronide
– Conjugation of bile acids to glycine/taurine
• Genetic polymorphisms of conjugating
enzymes poorly understood.
• Inducibility of conjugating enzymes poorly
understood.
Drug/Xenobiotic Elimination
• Once drugs have been altered by Phase I
and Phase II enzymes, they may be
excreted by:
• Biliary Excretion
• Renal Excretion
Organic molecules
(especially once made
more hydrophilic by
Phase I and Phase II
reactions) are often
rapidly excreted in bile.
Examples: bilirubin
bile acids
Some drugs/xenobiotics
are transported without
any biotransformation
step.
Common Theme
• Liver uses similar mechanisms to handle
endogenous and xenobiotic compounds
• FYI: these enzymes and transporters
appear to be coordinately regulated by
orphan nuclear receptors
Liver and Intestine Handling of Drugs/Xenobiotics
Not exclusive to liver: Gut may also handle drugs/xenobiotics
Drug
Drug
MDR
(P-gp)
Metabolite
Drug
Drug
MDR
(P-gp)
Drug
Metabolite
Drug
CYP
CYP
ER
ER
Hepatocyte
Enterocyte
Both liver and gut can eliminate drugs by metabolism
and/or apical excretion.
Reduce any or all and blood concentration will rise.
Drug-Drug Interactions:
Various Issues
• Competitive inhibition of CYP
– drug A increases toxicity of drug B
• Induction of CYP
– increased elimination of drug
– increased production of toxic metabolites
• Applicable to environmental and “natural”
products as well as drugs
Case Presentation
• 23 year old man underwent cardiac
transplantation.
• Begun on usual doses of cyclosporin A (6
mg/kg/day) and levels were therapeutic
for 2 days.
• Then developed renal failure and
seizures consistent with acute cyclosporin
A toxicity - blood levels of CsA were high.
Case Continued
• Dose was reduced and therapeutic blood
levels were re-established
• However, 6 weeks after surgery his blood
levels had fallen to subtherapeutic levels
and dose had to be increased again.
• WHY?
Cytochrome P450
Metabolism/Competition
A
B
CYP1A2
CYP2D6
D
C
CYP3A4
ENDOPLASMIC RETICULUM
Drug Interactions and CYP3A4
Absence of competition -
CYP3A4
Drug:
Unaltered
Cyclosporin
Cyclosporin A
Cyclosporin
Metabolites
Cytochrome P450 Metabolism
A
B
CYP1A2
CYP2D6
CsA
Keto
CYP3A4
ENDOPLASMIC RETICULUM
Drug Interactions and CYP3A4
Ketoconazole
Nicardipine
CYP3A4
Drug
Unaltered
Cyclosporin A
Cyclosporin A
Metabolites
Our Case
• Patient has Cyclosporin A toxicity and high
blood levels 2 days after transplant.
• Not likely due to genetically low levels of
CYP3A4 as six weeks later his blood levels
were low.
• More likely high levels due to simultaneous
administration of a competing drug ketoconazole for suspected fungal infection.
Not Just a Problem with Conventional Drugs
Induction of CYP Enzymes
• CYP substrates can induce CYP gene
transcription, increasing liver capacity for
drug metabolism.
• Induction is usually specific for one or
only a few CYPs.
• Induction likely occurs through broadspecificity orphan nuclear receptors.
Example:
CYP3A4 Induction by rifampin
pre
(6 mo)
pre
1 day
7 days
Rifampin
post
(3 days)
Drug Interactions and CYP3A4:
Induction of CYP Enzymes
Antiseizure drugs
Rifampin
St. John’s Wort
CYP3A4
Drug
Drug
Metabolites
Our Case: Subtherapeutic cyclosporin levels 6 weeks
after discharge
Antiseizure drugs:
Phenobarbital
Dilantin
CYP3A4
Cyclosporin
Unaltered
Cyclosporin
Metabolites
Approach to Drug-Drug
Interactions
• Be aware of the problem
• Look up potential interactions
– computer databases
• Monitor blood levels of drug
• Monitor biologic action
• Monitor for known toxicities
Effects of Drugs on the Liver:
Drug-Induced Liver Disease
• Many types of injury
• Some predictable
– drug-drug interactions
• Most rare and not easily predictable
– idiosyncratic/metabolic/genetic
• Therapeutic misadventure
Drug-Induced Liver Disease
• Hepatocellular injury
– toxic metabolite: isoniazid, acetaminophen
• Autoimmune hepatocellular injury
– halothane hepatitis
• Cholestatic liver injury
– estrogen
Acetaminophen Metabolism
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Glutathione
conjugation
CYP2E1
(CYP3A4, CYP1A2)
Toxic metabolites (NAPQI)
Covalent binding
oxidative stress
Hepatocyte damage
Excretion
Safe, useful and
widely available,
but………..
Andy Melton, Flickr
A little may be good,
however a lot may
be bad.
Acetaminophen Metabolism: High
Dose
Acetaminophen
Overdose
Glucuronidation
Sulfation
Saturated
Stable
Metabolites
Excretion
Glutathione
conjugation
CYP2E1
Toxic metabolites (NAPQI)
Covalent binding
oxidative stress
Hepatocyte damage
N-acetylcysteine
(antidote to overdose)
Liver Damage Due to Toxic
Doses of Acetaminophen
• What part of the liver will be affected?
• Hepatocellular versus cholestatic
disease?
Acetominophen Hepatotoxicity
Portal
Tract
Pericentral
Hepatocyte
necrosis
Mechanism of Drug-Induced Autoimmune Liver Disease
Halothane Hepatitis
F
[
F--C--C=O
[ [
F O
[
Tolerent
<5%
Hapten =
Autoimmunity
Cyp
2E1
Cyp
2E1
Plasma Membrane
F
[
F--C--C=O
[ [
F OH
F Cl
[ [
F--C--C--H
[ [
F Br
>95%
ER
F
[
F--C--C=O
[ [
F O
[
Cyp
2E1
Cyp
2E1
ER
Neoantigen
Drug-induced Cholestatic Liver
Disease
• Estrogen
– specific effect on bilirubin and bile acid
transport
– discussed earlier in the week
Drug-Induced Liver Injury
•
•
•
•
•
Bile duct injury
Steatosis and steatohepatitis
Vascular injury/veno-occlusive disease
Neoplasms
Other rare types of liver disease
Therapeutic Misadventure
• Patient uses a drug at a “safe” dose.
• In the presence of an environmental
change, toxicity develops.
• Example:
acetaminophen and alcohol
Drug-Induced Liver Disease:
Case
47 year old known alcoholic admitted through ER with
jaundice and disorientation.
1 week ago he developed abdominal pain, he thought this was
due to alcohol so stopped drinking.
Took over-the-counter pain reliever for several days and
abdominal pain subsided.
Labs: Bilirubin
5.7 mg/dl
Alk Phos
210 IU/l
AST
10,310 IU/l
ALT
12,308 IU/l
PT
41 seconds
What type of liver problem does he have?
Acetaminophen Metabolism
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Glutathione
conjugation
CYP2E1
(CYP3A4, CYP1A2)
Toxic metabolites (NAPQI)
Covalent binding
oxidative stress
Hepatocyte damage
Excretion
A Potentially Lethal
Combination
Andy Melton, Flickr
Jerry Lai, Flickr
Effects of Alcohol on
Acetaminophen:
Drugs that Induce CYP2E1
• Isoniazid (INH)
• Phenobarbital
• Ethanol !!!
Acetaminophen Metabolism After Chronic
EtOH Use and with Fasting
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Glutathione
conjugation
CYP2E1
Toxic metabolites (NAPQI)
EtOH
Covalent binding
oxidative stress
Hepatocyte damage
Fasting
Excretion
Second Case
• Patient was a chronic alcoholic
• Chronically induced CYP 2E1
• Poorly nourished with low glutathione
levels
• Developed mild pancreatitis and took
acetaminophen while fasting
• Developed acute massive hepatic
necrosis
Approach to Drug-Induced
Liver Disease
• Always consider drugs/herbs/toxins in the
differential diagnosis of ALL liver
diseases
• Stop all drugs/agents immediately
• Look it up - check computer databases
and textbooks
Approach to Prevention of
Drug-Induced Liver Disease
• Be aware of problem and check
databases for known interactions
• Screen for initial mild liver damage before
it becomes severe - AST/ALT most
used
• Holy Grail: tailor drugs to patient’s
genetic/environmental/drug profile
Effect of Liver Failure or Cirrhosis
on Drug Disposition
• Drug biotransformation and elimination is
a liver function
– Drug elimination may be reduced in patients
with significant liver dysfunction - thus blood
levels may be higher for longer (toxicity vs
effectiveness?)
• Low clearance drugs
– often relatively little effect until end stage
liver failure/cirrhosis as drug metabolism is
relatively well preserved
Effect of Liver Failure or Cirrhosis
on Drug Disposition
• Specifically: High clearance drugs
– affected by portosystemic shunts - markedly
increased systemic bioavailability of oral
drugs
– drug levels in blood may get very high
Cirrhotic patients with
portosystemic shunts:
Blood from intestines
bypasses the liver,
delivering much more
of orally administered
drugs to the systemic
circulation.
Thus, systemic bioavailability
of orally administered high
clearance drugs is much
greater.
Effect of Liver Failure or Cirrhosis
on Drug Disposition
• Cirrhosis does not:
– increase susceptibility to idiosyncratic drug
reactions
– increase likelihood of autoimmune-mediated
drug reactions
Approach to Drug Use in
Patients with Significant Liver
Dysfunction
• Reduce oral doses of high extraction
drugs such as propranolol
• Monitor the biologic effect of the drug
(heart rate)
• Monitor blood levels (if possible)
• Start with low dose and titrate up to
biologic effect or blood level
Summary
• Drugs/xenobiotics and liver intersect in
many ways
• Suspect problem(s)
• Look up data
Additional Source Information
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Slide 51: Andy Melton, Flickr, http://www.flickr.com/photos/trekkyandy/216437482/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.en
Slide 62: Andy Melton, Flickr, http://www.flickr.com/photos/trekkyandy/216437482/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.en; Jerry Lai,
http://www.flickr.com/photos/jerrylai0208/6127164522/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/2.0/deed.en