CHAP 2 Flashcards
Functionalization reactions
• Include: Oxidative, reductive and hydrolytic biotransformations
• Purpose is to introduce a functional polar group(s) (Ex: OH, COOH, NH2, SH) into the xenobiotic molecule to produce a more-water soluble compound
PHASE I
Mixed Function Oxidase System
> Cytochrome P450 (wavelength)
- responsible for transferring an oxygen atom to the substrate
-contains iron and copper
OXIDATION
What are the examples of CYP450?
CYP3A4
CYP2D6
- responsible for transferring an oxygen atom to the substrate
-contains iron and copper
Cytochrome P450 (wavelength)
most dominant isoform of Cytochrome P450 in the liver
CYP3A4
example of CYP450 that is used as antidepressants
CYP2D6
The ____________ are heme proteins.
The CYP enzymes are heme proteins.
The CYP enzymes are heme proteins. The heme portion is an iron-containing porphyrin called __________________ , and the protein portion is called ____________
The CYP enzymes are heme proteins. The heme portion is an iron-containing porphyrin called protoporphyrin IX, and the protein portion is called apoprotein.
plays an important role in the metabolism of many compounds containing carbonyl, nitro and azo group
• carbonyl compounds are converted to alcohol derivatives while nitro and azo are converted to amino derivatives
Reduction
for drugs containing the ester/amide functionality
Hydrolysis
Conjugation Reactions
• Purpose is to attach small, polar, and ionizable endogenous compounds such as glucuronic acid, sulfate, glycine, and other amino acids to the functional handles of phase I metabolites or parent compounds that already have suitable existing functional groups to form water-soluble conjugated products.
• Conjugated metabolites are readily excreted in the urine and are generally devoid of pharmacological activity and toxicity in humans.
- Methylation and Acetylation
- Glutathione (GSH) Conjugation
PHASE II
- terminate or attenuate biological activity
Methylation and Acetylation
- protects the body against chemically reactive compounds and metabolites.
Glutathione (GSH) Conjugation
Most common
• Morphine, Paracetamol, Chloramphenicol (Gray Baby Syndrome)
• Glucuronyl transferase
GLUCURONIDATION
• Well-developed in infants • Ex: Paracetamol
SULFATE CONJUGATION
• used to conjugate carboxylic acids
• Ex: Benzoic acid to hippuric acid
Glycine & Glutamine Conjugation
• an important pathway by which chemically reactive electrophilic compounds are detoxified
• free radical scavenger
Glutathione or Mercapturic Acid Conjugation
• a tripeptide (glutamyl- cysteinylglycine)
Glutathione or GSH
• important for drugs containing primary amino groups
• Hydralazine (SLE), Isoniazid (Peripheral Neuropathy), Sulfonamides (crystalluria)
uses N-acetyltransferase enzyme
• primary function is to terminate pharmacological activity and detoxification
Acetylation
• autoimmune disease; more common in female
• antigen and antibody complex
SLE-like symptom - “Malar Rash or Butterfly Rash”
• PIMCH - Procainamide, Isoniazid, Methyldopa, Chlorpromazine, Hydralazine
SLP
SLE stands for?
Systemic Lupus Erythematosus
• inactivation of physiologically active biogenic amines
• does not lead to polar or water-soluble metabolites but are pharmacologically inactive
METHYLATION
the most important organ in drug metabolism and detoxification of endogenous and exogenous compounds.
LIVER
important site especially for orally administered drug
• contains CYP3A4 isozyme and P-glycoprotein that can capture drug and secrete it back into the intestinal tract.
Intestinal Mucosa
• orally administered drugs pass through the liver and are susceptibe to hepatic metabolism before reaching the bloodstream
• can decrease oral bioavailability
First-pass effect
Drugs Metabolized Extensively by First-Pass Effect
• Isoproterenol
• Lidocaine
• Meperidine
• Morphine
• Nitroglycerin
• Pentazocine
• Propoxyphene
• Propanolol
• Salicylamide
Enzyme inhibitor drugs:
- Sodium valproate
- Isoniazid
- Cimetidine
- Ketoconazole
- Fluconazole
- Alcohol.binge drinking
- Chloramphenicol
- Erythromycin
- Sulfonamides
-Ciprofloxacin
-Omeprazole
-Metronidazole
-Grapefruit juice
Enzyme inducer drugs:
- Carbemazepines
- Rifampicin
- Alcohol (chronic)
- Phenytoin
- Griseofulvin
- Phenobarbital
- Sulphonylurea
