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Drug Induce Liver Injury

(DILI)

Departement of Pharmacology and Clinical Pharmacy


Faculty of Pharmacy, Universitas Padjadjaran
The Liver

Stores vitamins, sugars, fats and other


nutrients from the food that you eat
Builds chemicals that your body needs to stay
healthy
Breaks down harmful substances, like alcohol
and other toxic (poisonous) chemicals
Removes waste products from your blood
Makes sure that your body has just the right
amount of other chemicals that it needs
Drugs and The Liver
Liver Disease

Drug-Drug
Drugs Interactions
LIVER
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?)
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
High Extraction Drugs/
Xenobiotics/ Endogenous Compounds

Nitroglycerine
Lidocaine
Propranolol
Bile Acids
Hepatic Drug Clearance

For Low Extraction Drugs:

Equation reduces to simple form:


ClH = fx unbound x ClINT
Low Extraction Drugs/ Endogenous
Compounds

Diazepam
Phenytoin
Theophylline
Bilirubin
Phase 1 Biotransformation and
Phase 2 Conjugation in Liver

O Sugar
OH
OH

Glucuronyl
CYP transferase

ER ER

Phase 1 Phase 2
Oxidative Conjugation to polar ligand
reactions Glucuronyl transferases
CYP-mediated Sulfotransferases
Glutathione-S- transferases
Contributions of Specific P450s to
Drug Metabolism

CYP3A4
CYP3A4
CYP2E1

CYP2D6
CYP2C*

CYP1A2
unknown

* multiple subfamily
members exist
Role: Production of an active drug
Biotransformation of an inactive pro-drug) to an active drug

pro-drug

active drug

Glucuronyl
OH 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
Role: Production of less-toxic metabolite
Conjugation of acetaminophen to UDP-glucuronic acid

NH-CO-CH3

NH-CO-CH3
UDP
+ Glucuronic acid O Glucuronic acid

OH UDP-glucuronyl
transferase

ER
CYP

ER
Drug Elimination

Once drugs have been altered by Phase I and Phase II


enzymes, they may be excreted by:

Biliary Excretion
Renal Excretion
Common Theme
Liver uses similar mechanisms to handle
endogenous and xenobiotic compounds
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
Cytochrome P450
Metabolism/Competition
B D
A C

CYP1A2 CYP2D6 CYP3A4

ENDOPLASMIC RETICULUM
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.
Also given ketoconazole for suspected fungal
infection.
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?
Drug Interactions and CYP3A4

Absence of competition -

CYP3A4

Drug: Unaltered
Cyclosporin
Cyclosporin A

Cyclosporin
Metabolites
Cytochrome P450 Metabolism

A B CsA Keto

CYP1A2 CYP2D6 CYP3A4

ENDOPLASMIC RETICULUM
Our Case: Subtherapeutic cyclosporin
levels 6 weeks after discharge

Ketoconazole

CYP3A4
Unaltered
Drug
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.
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 broad-specificity
orphan nuclear receptors.
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 Injury

Hepatocellular injury
toxic metabolite: isoniazid, acetaminophen
Autoimmune hepatocellular injury
halothane hepatitis
Cholestatic liver injury
estrogen
DILI Incidence
10 fold increase in No. of reported cases between 1964-
1973 in Japan

10% of cases of hepatitis in a major hepatology center in


France

20% of instances of jaundice among geriatric population


in USA

9% of hospitalized patients with AST 400 IU/L in a


survey in UK

25%-40% of fulminent hepatic failure


DILI:
Predictable
Dose related
Intrinsically hepatotoxic drugs
Acute (hours)
Injury pattern is usually necrosis
Clinically Fulminant (Acute Hepatitis)
Example: Acetaminophine

Unpredictable
Not dose related
Rare 0.01-1.0 %
Weeks to months after ingestion of drug
Idiosyncratic
Immune mediated idiosyncrasy (Hypersensitivity)
Rash
Fever
Arthragia
Eosinophilia
Example: Phenytoin, Sulfonamides, Valproate

Metabolic idiosyncrasy (Production of toxic metabolites)


Example: INH, Ketoconazole, and Diclofenac
Diagnosis of DILI

High index of suspicion


Abnormalities in hepatic associated enzymes
Hepatitis like symptoms
Jaundice
Drug history
Dose
Duration of therapy
Time between initiating therapy and the development of hepatic injury
(latency)
Exclusion of other causes of liver diseases 2%-5% of
Hepatitis B
general
Hepatitis C
population
Alcoholic liver diseases
Non alcoholic fatty liver diseases
Hemochromatosis
Diagnosis of DILI

Extrahepatic manifestations

Hypersensitivity reactions
Fever
Rash
Arthralgias
Esinophelia

Unique clinical syndromes


Risk Factors For Susceptibility to DILI

Methotrexate Acetaminophen
Alcohol Alcohol
Obesity Fasting
D.M INH
Chronic hepatitis
Valproate
INH Young age
HBV,HCV,HIV Anticonvulsants
Alcohol
Older age Diclofenac
Female Female
Osteoarthritis
Risk Factors For Susceptibility to DILI

Sulfonamide Rifampicin
HIV Slow acetylators
Slow acetylator INH
Genetic defect in defense
Pyrazinamide
Anticonvulsats Slow acetylators
Genetic defect in INH
detoxification
Acetaminophen Metabolism
Glucuronidation
Sulfation
Acetaminophen Stable
Excretion
Metabolites

CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation

Toxic metabolites (NAPQI)

Covalent binding
oxidative stress

Hepatocyte damage
Acetaminophen Metabolism:
High Dose
Glucuronidation
Acetaminophen Sulfation
Stable
Overdose Saturated Metabolites
Excretion

Glutathione
CYP2E1 conjugation

Toxic metabolites (NAPQI)

N-acetylcysteine
Covalent binding (antidote to overdose)
oxidative stress

Hepatocyte damage
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
Acetaminophen Stable
Excretion
Metabolites

CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation

Toxic metabolites (NAPQI)

Covalent binding
oxidative stress

Hepatocyte damage
A Potentially Lethal
Combination

Andy Melton, Flickr Jerry Lai, Flickr


Acetaminophen Metabolism After
Chronic EtOH Use and with Fasting
Glucuronidation
Sulfation
Stable
Acetaminophen Metabolites
Excretion

CYP2E1 Glutathione
conjugation

Toxic metabolites (NAPQI)

EtOH
Fasting
Covalent binding
oxidative stress

Hepatocyte damage
Drugs that Induce CYP2E1

Isoniazid (INH)
Phenobarbital
Ethanol !!!
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 patients
genetic/environmental/drug profile
Approach to Drug Use in Patients
with Significant Liver Dysfunction

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
Regulatory actions due to DILI (1995-2006)
Withdrawals Second Line Warnings
bromfenac felbamate Acetaminophen
troglitazone leflunomide
tolcapone
nefazodone
pemoline trovafloxacin Nevirapine
pyrazinamide/rifampin
terbinafine
valproic acid
zifirlukast
atomoxetine
interferon 1b 1b and 1a
saquinavir
infliximab
bosentan
telithromycin
http://www.fda.gov/medwatch/safety.htm (kava, lipokinex)
Of the 23 drugs that have
undergone withdrawal, restriction
or warnings

19/23 (82%) were associated with acute


idiosyncratic hepatocellular injury
Prescription of DILI to patients with
liver disease
Prescription of DILI to patients with
liver disease

If necessary , need special treatments:


1. Dose adjustment
2. Administration of other compounds
Prescription of DILI to patients with
liver disease in a Public Hospital in
Tasikmalaya 2010-2011 (52 patients)
Prescription of DILI to patients with
liver disease in a Public Hospital in
Bekasi 2010-2011 (69 patients)
Prescription of DILI to patients with liver
disease in a Private Hospital in Eastern
Bandung 2010-2011 (153 patients)
Prescription of DILI to patients with liver
disease in a Private Hospital in Northern
Bandung 2010-2011 (103 patients)
Community
Clinical Pharmacist