1. 1 Author(s): Rebecca W. Van Dyke, M.D., 2012
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3. M2 GI Sequence Drugs and the Liver
Rebecca W. Van Dyke, MD
Winter 2012

4. 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.

5. Industry Relationship Disclosures Industry Supported Research and Outside Relationships
None

6. Drugs and the Liver Liver Disease Drug-Drug Interactions Drugs LIVER
Drug Elimination
Drug Metabolites
(the good, the bad and the ugly)

7. 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?)

8. of potentially undesirable chemicals/xenobiotics (an eternal problem):
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.

9. 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

11. Hepatic Drug Clearance
For High Extraction Drugs:
Equation reduces to simple form:
ClH = Q

12. Effect of Efficient Extraction by Hepatocytes in Series
Portal
Hepatic
Vein
Vein
Input
Output
100% 5%

13. High Extraction Drugs/ Xenobiotics/ Endogenous Compounds
Nitroglycerine
Lidocaine
Propranolol
Bile Acids

14. 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.

15. Hepatic Drug Clearance
For Low Extraction Drugs:
Equation reduces to simple form:
ClH = fx unbound x ClINT

16. Effect of Low Extraction Efficiency by Hepatocytes in Series
Portal
Hepatic
Vein
Vein
Input
Output
100%
80%

17. 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.

18. 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)

19. Steps in Liver Biotransformation and Elimination of Drugs - II
Biliary excretion
Efflux to blood for eventual renal excretion

20. Liver Biotransformation and Elimination of Drugs - III
These processes exist for endogenous compounds, not just for drugs and xenobiotics

21. Phase 1 and Phase 2 Biotransformation in Liver
Glucuronyl
transferase OH O
Sugar OH
CYP ER
Phase 1
Phase 2
Oxidative
Conjugation to polar ligand
reactions
Glucuronyl transferases
CYP-mediated
Sulfotransferases
Glutathione-S-
transferases

22. 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)

23. Fe
Anatomy of the
Cytochromes
P450, a.k.a. CYP

24. Contributions of Specific P450s to Drug Metabolism
CYP1A2
CYP2E1
CYP3A4
CYP2C*
CYP2D6
unknown
* multiple subfamily
members exist

25. 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

26. Role: Production of an active drug:
Biotransformation of an inactive pro-drug) to an active drug
CYP3A4 ER OH
pro-drug
active drug ER
Glucuronyl
transferase

27. 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

28. + Conjugation of acetaminophen to UDP-glucuronic acid NH-CO-CH3ER
UDP-glucuronyl
transferase
Glucuronic acid O
NH-CO-CH3 OH
NH-CO-CH3
Glucuronic acid
UDP +
CYP ER

29. 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.

30. Drug/Xenobiotic Elimination
Once drugs have been altered by Phase I and Phase II enzymes, they may be excreted by:
Biliary Excretion
Renal Excretion

31. 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.

32. 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

33. Liver and Intestine Handling of Drugs/Xenobiotics
Not exclusive to liver: Gut may also handle drugs/xenobiotics
Drug
Hepatocyte
CYP ER
Drug
Metabolite
MDR
(P-gp)
MDR
(P-gp)
Drug
Metabolite
Drug
CYP ER
Enterocyte
Both liver and gut can eliminate drugs by metabolism
and/or apical excretion.
Reduce any or all and blood concentration will rise.

34. 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

35. 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.

36. 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?

37. Cytochrome P450 Metabolism/CompetitionD A B
CYP1A2
CYP3A4
CYP2D6
ENDOPLASMIC RETICULUM

38. Drug Interactions and CYP3A4
Absence of competition -
CYP3A4
Drug:
Cyclosporin A
Unaltered
Cyclosporin
Cyclosporin
Metabolites

39. Cytochrome P450 Metabolism
Keto
CsA A B
CYP1A2
CYP3A4
CYP2D6
ENDOPLASMIC RETICULUM
ENDOPLASMIC RETICULUM

40. Drug Interactions and CYP3A4
Ketoconazole
Nicardipine
CYP3A4
Unaltered
Cyclosporin A
Drug
Cyclosporin A
Metabolites

41. 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.

42. Not Just a Problem with Conventional Drugs

43. 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.

44. Example: CYP3A4 Induction by rifampin
pre
(6 mo)
pre
1 day
7 days
post
(3 days)
Rifampin

45. Drug Interactions and CYP3A4: Induction of CYP Enzymes
Antiseizure drugs
Rifampin
St. John’s Wort
CYP3A4
Drug
Drug
Metabolites

46. Our Case: Subtherapeutic cyclosporin levels 6 weeks after discharge
Antiseizure drugs:
Phenobarbital
Dilantin
CYP3A4
Unaltered
Cyclosporin
Cyclosporin
Metabolites

47. 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

48. 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

49. Drug-Induced Liver Disease
Hepatocellular injury
toxic metabolite: isoniazid, acetaminophen
Autoimmune hepatocellular injury
halothane hepatitis
Cholestatic liver injury
estrogen

50. Acetaminophen Metabolism
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Excretion
Glutathione
conjugation
CYP2E1
(CYP3A4, CYP1A2)
Toxic metabolites (NAPQI)
Covalent binding
oxidative stress
Hepatocyte damage

51. Safe, useful and
widely available,
but………..
Andy Melton, Flickr

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

53. Acetaminophen Metabolism: High Dose
Glucuronidation
Sulfation
Acetaminophen
Overdose
Stable
Metabolites
Excretion
Saturated
Saturated
Glutathione
conjugation
CYP2E1
Toxic metabolites (NAPQI)
N-acetylcysteine
(antidote to overdose)
Covalent binding
oxidative stress
Hepatocyte damage

54. Liver Damage Due to Toxic Doses of Acetaminophen
What part of the liver will be affected?
Hepatocellular versus cholestatic disease?

55. Acetominophen Hepatotoxicity
Portal
Tract
Pericentral
Hepatocyte
necrosis

56. Mechanism of Drug-Induced Autoimmune Liver Disease
Halothane Hepatitis
Hapten = F --
C--C=O [ O
Tolerent
Autoimmunity
Cyp
Cyp
<5%
2E1
2E1
Plasma Membrane F
F--C--C--H F [ Cl Br F [ [
F--C--C=O [ [
F--C--C=O [ [ F O
Neoantigen F OH [
Cyp
Cyp
>95%
2E1
2E1 ER ER

57. Drug-induced Cholestatic Liver Disease
Estrogen
specific effect on bilirubin and bile acid transport
discussed earlier in the week

58. Drug-Induced Liver Injury
Bile duct injury
Steatosis and steatohepatitis
Vascular injury/veno-occlusive disease
Neoplasms
Other rare types of liver disease

59. Therapeutic Misadventure
Patient uses a drug at a “safe” dose.
In the presence of an environmental change, toxicity develops.
Example: acetaminophen and alcohol

60. 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?

61. Acetaminophen Metabolism
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Excretion
Glutathione
conjugation
CYP2E1
(CYP3A4, CYP1A2)
Toxic metabolites (NAPQI)
Covalent binding
oxidative stress
Hepatocyte damage

62. A Potentially Lethal
Combination
Andy Melton, Flickr
Jerry Lai, Flickr

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

64. Acetaminophen Metabolism After Chronic EtOH Use and with Fasting
Glucuronidation
Sulfation
Stable
Metabolites
Acetaminophen
Excretion
Glutathione
conjugation
CYP2E1
Toxic metabolites (NAPQI)
EtOH
Fasting
Covalent binding
oxidative stress
Hepatocyte damage

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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.

71. 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

72. 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

73. Summary Drugs/xenobiotics and liver intersect in many ways
Suspect problem(s)
Look up data

74. Additional Source Information
for more information see:
Slide 51: Andy Melton, Flickr, CC:BY-SA,
Slide 62: Andy Melton, Flickr, CC:BY-SA, Jerry Lai, CC:BY-SA,