02.06.12(a): Drugs and the Liver

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

• 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

Liver Disease

Drug Metabolites (the good, the bad and the ugly)

Drug Elimination

Drugs and the Liver

Drug-Drug Interactions

LIVER

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?)

Absorbed Intact

Absorbed and Metabolized

Not Absorbed

Absorbed and Excreted

Taken up Metabolized Conjugated Returned to blood Excreted in bile

Drug Absorption Gut/Liver Barrier FunctionBarriers to uptake

of potentially undesirablechemicals/xenobiotics(an eternal problem):

1. Gut mucosa2. Liver

Barrier consists of multiplesteps.Not all xenobiotics are affectedby 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 ofdrug 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 VeinInput

100%

Hepatic Vein

Output

5%

High Extraction Drugs/Xenobiotics/ Endogenous

Compounds

• Nitroglycerine• Lidocaine• Propranolol• Bile Acids

Rapid uptake and elimination by hepatocytes

Drug Absorption First Pass Clearance

Low systemic bioavailability of rapid clearance drugs

High Extraction Drugs:

Drugs/xenobiotics rapidlycleared in a single passthrough the liver.

Consequences can be good or bad:

Oral administration of drugs/xenobiotics is inefficient –must administer IV/IM.

However, enterohepaticcirculation of bile acids isefficient.

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 VeinInput

100%

Hepatic Vein

Output

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

CYP

ER

OH

ER

Glucuronyl transferase

OH O Sugar

Phase 1 Phase 2Oxidative reactions CYP-mediated

Conjugation to polar ligand Glucuronyl transferases Sulfotransferases Glutathione-S-transferases

Phase 1: Biotransformation• Direct modification of primary structure• Cytochromes P450

– Oxidative reactions– Add reactive/hydrophilic groups (-OH)

• 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 theCytochromes P450, a.k.a. CYP Fe

CYP1A2

CYP2E1CYP3A4CYP3A4

CYP2C*CYP2C*CYP2D6CYP2D6

unknown

* multiple subfamily members exist

Contributions of Specific P450s to Drug Metabolism

CYPs: Role in breakdown of active drugGenetic variations: Desipramine Kinetics Due

to Polymorphisms in CYP 2D6

slow ExtensiveMetabolizer(most common)

PoorMetabolizer

TIME since administration

log plasmaDesipramineconcentration

fast ExtensiveMetabolizer

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

Role: Production of an active drug:Biotransformation of an inactive pro-drug) to an active drug

ER

Glucuronyl transferase

CYP3A4

ER

OH

pro-drug

active drug

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

CYP

ER

Conjugation of acetaminophen to UDP-glucuronic acid

ER

UDP-glucuronyl transferase

Glucuronic acidO

NH-CO-CH3

OH

NH-CO-CH3

Glucuronic acid

UDP

+

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

P-glycoprotein (MDR)

Daunomycin Verapamil Cyclosporine

ATP

ADPBile acids

ATPA

DP

Conjugated bilirubin Glutathione S-conjugates other conjugated organic anions

Bile Canaliculus

Hepatocyte cytosol

Bile acid transporter

Canalicular Organic Compound Efflux Pumps

ATPAD

P

MRP-2 organic anion transporter

Organic molecules(especially once mademore hydrophilic byPhase I and Phase IIreactions) are oftenrapidly excreted in bile.

Examples: bilirubin bile acids

Some drugs/xenobioticsare transported withoutany biotransformationstep.

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/XenobioticsNot exclusive to liver: Gut may also handle drugs/xenobiotics

Enterocyte

CYP

ER

DrugMetabolite

MDR (P-gp)

Drug

Drug

Hepatocyte

CYP

ER

DrugMetabolite

MDR (P-gp)

Drug

Drug

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

ENDOPLASMIC RETICULUM

A

CYP1A2 CYP3A4CYP2D6

B CD

Drug Interactions and CYP3A4

Drug:Drug:

Cyclosporin ACyclosporin A

CyclosporinCyclosporinMetabolitesMetabolites

UnalteredUnalteredCyclosporinCyclosporin

Absence of competition -

CYP3A4

Cytochrome P450 Metabolism

ENDOPLASMIC RETICULUMENDOPLASMIC RETICULUM

CsA KetoA

CYP1A2 CYP3A4CYP2D6

B

Drug Interactions and CYP3A4

CYP3A4CYP3A4

DrugDrug

Cyclosporin ACyclosporin A

MetabolitesMetabolites

UnalteredUnalteredCyclosporin ACyclosporin A

KetoconazoleKetoconazoleNicardipineNicardipine

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.

St John’s Wort

ENDOPLASMIC RETICULUM

Coumadin

B

Result: Increased blood coumadin Increased prothrombin time Spontaneous bleeding

Drug-Drug Interactions Leading to Toxicity

A

CYP1A2 CYP3A4CYP2D6

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 broad-specificity orphan nuclear receptors.

Example:CYP3A4 Induction by rifampin

prepre(6 mo)(6 mo)

prepre 1 day1 day 7 days7 days postpost(3 days)(3 days)

RifampinRifampin

Drug Interactions and CYP3A4:Induction of CYP Enzymes

CYP3A4CYP3A4DrugDrug


DrugDrug

Antiseizure drugsAntiseizure drugsRifampinRifampin

St. JohnSt. John’’s Worts Wort

Our Case: Subtherapeutic cyclosporin levels 6 weeks after discharge

CYP3A4CYP3A4Cyclosporin Cyclosporin


UnalteredUnalteredCyclosporinCyclosporin

Antiseizure drugs:Antiseizure drugs:PhenobarbitalPhenobarbital

DilantinDilantin

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

AcetaminophenAcetaminophen

GlucuronidationGlucuronidationSulfationSulfation

Toxic metabolites (NAPQI)Toxic metabolites (NAPQI)

CYP2E1CYP2E1(CYP3A4, CYP1A2)(CYP3A4, CYP1A2)

StableStableMetabolitesMetabolites ExcretionExcretion

Covalent bindingCovalent bindingoxidative stressoxidative stress

Hepatocyte damageHepatocyte damage

GlutathioneGlutathioneconjugationconjugation

Safe, useful and widely available,

but………..

Andy Melton, Flickr

A little may be good,however a lot may be bad.

Acetaminophen Metabolism: High Dose

AcetaminophenAcetaminophenOverdoseOverdose Saturated



CYP2E1CYP2E1





Saturated

N-acetylcysteineN-acetylcysteine(antidote to overdose)(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

PericentralHepatocytenecrosis

PortalPortalTractTract

Mechanism of Drug-Induced Autoimmune Liver DiseaseHalothane Hepatitis

Tolerent

Plasma Membrane

ER

>95%

F--C--C--H

F [

[ F

Cl [

[ Br

F--C--C=O

F [

[ F

[ OH

Hapten =

ER

Autoimmunity

F--C--C=O

F [

[ F Neoantigen

[ O [

F--C--C=O

F [

[ O [

[ F

Cyp 2E1<5%

Cyp 2E1

Cyp 2E1

Cyp 2E1

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 withjaundice 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 andabdominal pain subsided.

Labs: Bilirubin 5.7 mg/dlAlk Phos 210 IU/lAST 10,310 IU/lALT 12,308 IU/lPT 41 seconds

What type of liver problem does he have?

Acetaminophen Metabolism




CYP2E1CYP2E1(CYP3A4, CYP1A2)(CYP3A4, CYP1A2)





A Potentially LethalCombination

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




CYP2E1CYP2E1





EtOHEtOHFastingFasting

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


• Specifically: High clearance drugs– affected by portosystemic shunts - markedly

increased systemic bioavailability of oral drugs

– drug levels in blood may get very high

Less efficient: Uptake Metabolism Conjugation Biliary excretion

Drug Absorption Effect of Cirrhosis

Large increase in systemic bioavailability - especially for rapid clearance drugs

Cirrhotic patients withportosystemic shunts:

Blood from intestinesbypasses the liver,delivering much moreof orally administereddrugs to the systemiccirculation.

Thus, systemic bioavailabilityof orally administered highclearance drugs is muchgreater.


• 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

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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

02.06.12(a): Drugs and the Liver

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