Drug Induced Liver Disease by w1F535

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									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 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?)
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                                                         Hepatic
Vein                                                            Vein
Input                                                          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                                                        Hepatic
Vein                                                           Vein
Input                                                         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




                                          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
      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 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      slow Extensive           Poor
                Metabolizer         Metabolizer              Metabolizer
                                    (most common)
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




                                      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
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
       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)
                                                                 Drug
                              MDR
          Metabolite          (P-gp)               Metabolite
   Drug                Drug                 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

                 B                      D
    A                      C




  CYP1A2       CYP2D6          CYP3A4




        ENDOPLASMIC RETICULUM
     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
       Drug Interactions and CYP3A4
                Ketoconazole
                 Nicardipine



                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.
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




         pre    pre   1 day    7 days     post
       (6 mo)                           (3 days)
                         Rifampin
  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
Acetaminophen                                  Stable
                                                             Excretion
                                               Metabolites


   CYP2E1                                Glutathione
(CYP3A4, CYP1A2)                         conjugation

           Toxic metabolites (NAPQI)

                    Covalent binding
                    oxidative stress

                   Hepatocyte damage
Safe, useful and
widely available,


but………..

                    Andy Melton, Flickr
A little may be good,
however a lot may
be bad.
    Acetaminophen Metabolism: High
                Dose
                    Glucuronidation
Acetaminophen          Sulfation
                                      Stable
Overdose            Saturated                             Excretion
                                      Metabolites


                                      Glutathione
  CYP2E1                              conjugation



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

                Hepatocyte damage
   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         Hapten =
                                                       [
           Tolerent                                F--C--C=O
                                                      [ [      Autoimmunity
                                                      F O
                                                          [


                               Cyp                       Cyp
                   <5%         2E1                       2E1
Plasma Membrane



                                                      F
                                         F            [
                     F Cl                          F--C--C=O
                     [ [                 [            [ [
                  F--C--C--H          F--C--C=O
                     [ [                 [ [          F O      Neoantigen
                                         F OH            [
                     F Br

                                Cyp                     Cyp
                     >95%       2E1                     2E1




                        ER                        ER
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
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
  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
Acetaminophen                                             Excretion
                                            Metabolites


   CYP2E1                             Glutathione
                                      conjugation

         Toxic metabolites (NAPQI)
  EtOH
                 Covalent binding
                                           Fasting
                 oxidative stress

                Hepatocyte damage
            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

								
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