Drug elimination 2: Liver

1
Drug elimination (2) Liver
Drug molecule
I
More hydrophilic metabolite
Conjugate
II
De-conjugation and reuptake (entero-hepatic
cycling)
Bile
Kidney
Intestines
Urine
Feces
2
Hepatic metabolism of morphine
Morphine UDP-glucuronide
Morphine-glucuronide UDP
Urine, bile
Morphine
Glucuronate
3
Hepatic metabolism of phenobarbital
4
Blood flow and bile flow in the liver tissue
to right heart
to bile bladder intestine
from intestine
5
UDP glucuronide
Glucose-6P Glucose-1P UDP-Glucose UDP-Glucur
onide Drug conjugates
Glycogen
Polysaccharides, proteoglycans
6
3-Phospho-adenosine-5-phosphosulfate (PAPS)
ATP
Sulfate
ATP
Pyrophosphate
ADP
PAPS
Sulfated polysaccharides and proteoglycans (e.g.
heparan sulfate, chondroitin sulfate), sulfated
sphingolipids (sulfatides)
Drug conjugates
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Drug biotransformation reactions

• Oxidative reactions
• N- and O-dealkylation
• Aliphatic and aromatic hydroxylation
• N-Oxidation and N-Hydroxylation
• Sulfoxide formation
• Deamination
• Desulfuration
• Conjugation reactions (with)
• Glucuronidation (UDP-Glucuronic acid)
• Acetylation (Acetyl-CoA)
• Conjugation with glycine
• Sulfate (PAPS)
• O-, N-, S-Methylation (S-Adenosylmethionine)
• Hydrolysis (Esters and amides)
• Reduction Azo reduction, nitro reduction

8
S-Adenosylmethionine (SAM)
ATP
Methionine
PP P
SAM
Methylation of DNA, Lipids,
Drug conjugates
9
Metabolism of Isoniazid (isonicotinic acid
hydrazide)
Acetyl-CoA
CoA
H2O
Acetylation of proteins
Isonicotinic acid
Acetylhydrazine
Liver toxicity
10
Genetic variability in INH acetylation
fast acetylators
slow acetylators
11
Cytochrome P450
12
Endoplasmic reticulum in the liver
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The microsomal cytochrome P450 system

• Cytochrome P450 enzymes
• Catalyze oxidation / hydroxylation of hydrophobic
  substrates, transferring a single oxygen atom
  from O2 to the substrate
• Use molecular oxygen as substrate and NADPH as a
  cosubstrate, to dispose of the second oxygen not
  transferred to the substrate
• Large gene superfamily, present in both
  prokaryotic and eukaryotic organisms
• In mammalian cells, present in both the ER and
  (with some variations) the mitochondrion
• Several dozen isoforms in humans, several of
  these involved in drug metabolism

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The microsomal cytochrome P450 system (2)

• Effects on drugs / poisons can be beneficial
  (inactivation, accelerated excretion) and harmful
  (conferment of toxic activity to inert compound)
• A single isoform CYP3A4 is responsible for
  the metabolism of gt 50 of the clinically
  prescribed drugs that do get metabolized in the
  liver
• CYP3A4 and several other isoforms are inducible
  prolonged drug application enhances expression
  and activity of enzyme in liver
• Induction may lead to accelerated metabolism of
  multiple drugs (not just the inducer itself).
  Example Rifampicin or phenytoin ? accelerated
  inactivation of contraceptive agents

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a)
b)
c)
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Propranolol as an example of drug transformation
in the liver
Propranolol
17
Mechanism of drug-mediated cytochrome P450
induction
D
hnf4
hnf4
mRNA
CYP 3A4
18
Benzopyrene as an example of harmful drug
metabolism
Mutation, carcinogenesis
CYP 1A1
19
Glutathione conjugation A detoxifying pathway
Glutathione-S-
Glutathione-S- Transferase
Urine
20
Metabolism of acetaminophen
21
Reductive drug metabolism

• NADPH- and NADH-dependent reductases
• CYP450 reductases, CYP450 itself
• Thioredoxin

Prontosil rubrum
22
Vicia faba (broad bean)
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Favism Catalytic depletion of glutathione by
isouramil
Glutathione peroxidase
spontaneous
spontaneous
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Uses of NADPH (4) Scavenging reactive oxygen
species
H2O2
G-SH HS-G
NADP
Glutathione reductase
Glutathione peroxidase
2 H2O
G-SS-G
NADPHH
25
Glucose-6P-dehydrogenase deficiency is one of the
most common enzyme defects

• Most patients healthy most of the time
  hemolytic crisis occurs upon exposure to drugs or
  diet components that cause enhanced formation of
  ROS
• Manifestation in the red cells because these
  cells lack protein synthesis no replacement of
  deficient protein molecules
• Affords partial protection against malaria
  similar to sickle cell anemia and other
  hemoglobinopathias

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Primaquine and G6PDH deficiency