Breakdown of xenobiotics by the enzymes of the upper digestive tract
Mouth
Stomach
Duodenum
Pancreas
Salivary Enzymes
Amylase
Lactoperoxidase
Acid phosphatase
Nonspecific esterase
Duodenal Enzymes
Sucrase
Maltase
Isomaltase
Lactase
Erepsin (proteins)
Pancreatic Enzyme
Stomach Enzymes
Pepsin
Gelatinase
Gastric Amylase
Gastric Lipase
Pancreatic Enzymes
Trypsin
Chymotrypsin
Steapsin (carbohydrates)
Carboxypolypeptidase (breaks peptides into amino acids)
Elastases
Nucleases
Pancreatic amylase
Major site of drug metabolism:
smooth endoplasmic reticulum of the liver cell
All tissue has ability to metabolize drugs especially
epithelial cells of GI tract, lungs, kidneys and skin
Drugs delivered intravenously and intramuscularly will eventually pass through the
liver
Physiological and pathological factors that influence drug metabolism:
Liver disease
Insufficient enterohepatic circulation
Pharmacogenetics
Phase I Drug Metabolism
Introduction or exposure of polar functional groups through oxidation, reduction and hydrolysis.
Phase II Drug Metabolism
Conjugation reactions at polar functional groups, attaching:
Glucuronic acid
Sulfonates
Glutathione
Amino acids
Cytochrome P450 Monooxygenase System
~525 amino acid proteins containing heme prosthetic group
P450
Pigment at 450 nm: Enzymes are red in color due to the heme cofactor
Major player in Phase I oxidative drug metabolism
Xenobiotic oxidation can detoxify, or activate
Makes xenobiotics more water soluble
Oxidation of xenobiotics can prepare them for further metabolism (Phase II)
Nomenclature for Cytochrome 450 Monooxygenase System
CYP-number-letter-number
CYP2
metabolizes drugs and steroids
CYP2A
Aromatic compounds
CYP2C
NSAIDS
A drug may be metabolized by a P450 enzyme and is called the
substrate for that P450
A drug may increase the rate of metabolism catalyzed by a P450 and is called an
inducer of that P450
A drug may decrease the rate of metabolism catalyzed by a P450 and is called an
inhibitor of that P450
A drug that induces or inhibits may or may not be
the substrate for that P450
CYP2D6 Substrates
Antidepressants
Antipsychotics
Beta blockers
Narcotics
CYP2D6 Inhibitors
Antidepressants
Antipsychotics
Cimetidine
CYP3A Substrates
Erythromycin
Ketoconazole
Theophylline (asthma drug, and methylated xanthine in black tea)
Glyburide
Protease Inhibitors
Statin drugs
CYP3A inhibitors
Antidepressants
Azole antifungals
Erythromycin
Protease Inhibitors
Grapefruit juice
CYP3A inducers
Phenobarbital
Rifampin (tuberculosis drug)
CYP1A2 Substrates
Propranolol
R-warfarin
Theophylline
Antidepressants
CYP1A2 Inhibitors
Quinolone antibiotics
Grapefruit juice
CYP1A2 Inducers
Omeprazole
Smoking
Charcoal-broiled meats
CYP2E1 Inducers
by Ethanol, metabolizes acetaminophen
CYP2E1 Substrates
Acetaminophen
Ethanol
CYP2E1 Inhibitors
Disulfiram (Antabuse)
CYP2C9 metabolizes
Warfarin: significant pharmacogenetic variability
CYP2C9 Substrates
S-warfarin
Nonsteroidal anti-inflammatory drugs
CYP2C9 Inducers
Rifampin (Tuberculosis drug)
CYP2C19 Substrates
Diazepam (Valium)
Omeprazole (Prilosec)
Propranolol
CYP2C19 Inhibitors
Fluoxetine (Prozac)
Sertraline (Zoloft)
Omeprazole
UDP-glucuronosyl transferase
Glucuronic Acid
Sulfotransferases
Sulfate
Glutathione-S-transferase
Glutathione or Mercapturic Acid
Methyltransferase
Methylation
N-acyltransferase
Amino Acids
Acetylases
Acetylation
Glycine conjugation seen in
mammals
Glutamine conjugation seen primarily in
primates
Amino acid is activated with ATP and coenzyme A to form
an acyl-coA complex
Conjugation with amino acids primarily occurs with
aromatic acids
Glutathione or Mercapturic Acid Conjugates
detoxify
electrophilic compounds that would otherwise be toxic
Acetylation occurs at
primary amines R-NH2
Acetylation Polymorphism
Caused by polymorphisms in N-acetyltransferase
Phase II Metabolism: Methylation
Used to inactivate catechols, phenols, amines, N-heterocyclic and thiol compounds
Polymorphism
the occurrence of a number of alternative forms within a section of a nucleic acid or protein molecule.