Author(s): Rebecca W. Van Dyke, M.D.

, 2012
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Drugs and the Liver

Rebecca W. Van Dyke, MD

Winter 2012

Learning Objectives
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.

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):

Drug Absorption
Gut/Liver Barrier Function

Taken up
Metabolized
Conjugated
Returned to blood
Excreted in bile

1. Gut mucosa
2. Liver
Barrier consists of multiple
steps.
Not all xenobiotics are affected
by each step.

Absorbed
Intact
Not Absorbed
Absorbed and
Excreted
Absorbed and
Metabolized

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
hepatic clearance (ClH)= liver blood flow

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.

Drug Absorption
First Pass Clearance
Low systemic bioavailability
of rapid clearance drugs

Rapid uptake and

elimination by
hepatocytes

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

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

Phase 1

Oxidative
reactions
CYP-mediated

Sugar

Glucuronyl
transferase

CYP
ER

ER

Phase 2

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)

Often rate-limiting, located in ER (endoplasmic retikculum)

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
CYP2D6
CYP2D6

CYP2E1
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
log plasma
Desipramine
concentration

slow Extensive
Metabolizer
(most common)

Poor
Metabolizer

TIME since administration

Implications for other drugs metabolized by CYP2D6: ??? Codeine

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

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

Canalicular Organic Compound

Efflux Pumps

Organic molecules
(especially once made
more hydrophilic by
Phase I and Phase II
reactions) are often
rapidly excreted in bile.

Hepatocyte
cytosol

P-glycoprotein
(MDR)

Bile
Canaliculus
Bile acid
transporter

Daunomycin
Verapamil
Cyclosporine
Bile acids

Examples: bilirubin
bile acids
Some drugs/xenobiotics
are transported without
any biotransformation
step.

Conjugated bilirubin
Glutathione S-conjugates
other conjugated organic anions

MRP-2
organic anion transporter

Common Theme
Liver uses similar mechanisms to handle
endogenous and xenobiotic compounds

Liver and Intestine Handling of Drugs/Xenobiotics

Not exclusive to liver: Gut may also handle drugs/xenobiotics
Drug
Drug
MDR
(P-gp)

Drug

Metabolite

Drug

MDR
(P-gp)
Drug

Drug

Metabolite

CYP

ER

CYP

Hepatocyte

ER

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

Some inhibitors of cytochrome P450 isozymes

1A2

2B6

2C8

2C19

2C9

2D6

2E1

fluvoxamine
ciprofloxacin

thiotepa
ticlopidine

gemfibrozil

lansoprazole
omeprazole2
pantoprazole
rabeprazole

fluconazole

bupropion
fluoxetine
paroxetine
quinidine

diethylHIV Antivirals:
dithiocarbamate indinavir
nelfinavir
ritonavir

duloxetine
terbinafine

clarithromycin
itraconazole
ketoconazole
nefazodone
saquinavir
telithromycin

trimethoprim
cimetidine
amiodarone
fluoroquinolones
furafylline
interferon
methoxsalen
mibefradil

glitazones
montelukast
quercetin

chloramphenicol
cimetidine
felbamate
fluoxetine
fluvoxamine
indomethacin
ketoconazole
modafinil
oxcarbazepine
probenicid
ticlopidine
topiramate

amiodarone
fenofibrate
fluvastatin
fluvoxamine
isoniazid
lovastatin
phenylbutazone
probenicid
sertraline
sulfamethoxazole
sulfaphenazole
teniposide
voriconazole
zafirlukast

amiodarone
cimetidine
sertraline
celecoxib
chlorpheniramine
chlorpromazine
citalopram
clemastine
clomipramine
cocaine
diphenhydramine
doxepin
doxorubicin
escitalopram
halofantrine
hydroxyzine
levomepromazine
methadone
metoclopramide
mibefradil

3A4,5,7

aprepitant
erythromycin
fluconazole
grapefruit juice
verapamil
diltiazem
cimetidine
amiodarone
chloramphenicol
delaviridine
diethyldithiocarbamate
fluvoxamine
gestodene

Some inducers of cytochrome P450 isozymes

1A2
chromosome 15

2B6
chromosome 6

broccoli
phenobarbital
brussel sprouts
rifampin
char-grilled meat
insulin
methylcholanthrene
modafinil
nafcillin
beta-naphthoflavone1
omeprazole
tobacco

2C8
chromosome 10

2C19
chromosome 10

2C9
chromosome
10

2D6
chromosome 22

2E1
chromosome
10

3A4,5,7
chromosome 7

rifampin

carbamazepine
norethindrone
NOT pentobarbital
prednisone
rifampin

rifampin
secobarbital

dexamethasone
rifampin

thanol
isoniazid

HIV Antivirals:
efavirenz
nevirapine
barbiturates
carbamazepine
efavirenz
glucocorticoids
modafinil
nevirapine
oxcarbazepine
phenobarbital
phenytoin
pioglitazone
rifabutin
rifampin
St. John's wort
troglitazone

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

CYP1A2

CYP2D6

CYP3A4

ENDOPLASMIC RETICULUM

Drug Interactions and CYP3A4

Absence of competition -

CYP3A4

Drug:
Cyclosporin A

Unaltered
Cyclosporin
Cyclosporin
Metabolites

Cytochrome P450 Metabolism

A

CYP1A2

CYP2D6

CsA

Keto

CYP3A4

ENDOPLASMIC RETICULUM

Drug Interactions and CYP3A4

Ketoconazole
Nicardipine

CYP3A4
Drug

Unaltered
Cyclosporin A

Cyclosporin A
Metabolites

Drug Interactions and CYP3A4:

Induction of CYP Enzymes
Antiseizure drugs
Rifampin
St. Johns Wort

Drug

CYP3A4

Drug

Metabolites

Our Case: Subtherapeutic cyclosporin levels 6 weeks

after discharge
Antiseizure drugs:
Phenobarbital
Dilantin

Cyclosporin

CYP3A4

Unaltered
Cyclosporin

Metabolites

Acetaminophen Metabolism: High Dose

Acetaminophen
Overdose

Glucuronidation
Sulfation

Stable
Metabolites

Saturated

CYP2E1

Sa

ed
t
ra
u
t

Excretion

Glutathione
conjugation

Toxic metabolites (NAPQI)

Covalent binding
oxidative stress
Hepatocyte damage

N-acetylcysteine
(antidote to overdose)

Effects of Alcohol on
Acetaminophen:
Drugs that Induce CYP2E1
Isoniazid (INH)
Phenobarbital
Ethanol !!!

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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