Metabolism/Biotransformation Flashcards
Define biotransformation
- changes lipid soluble/non-polar compounds -> H2O soluble/polar compounds so they can be excreted
What happens if biotransformation can’t occur?
Compounds/drugs remain in circulation for a long time -> toxic rxns
Pharmacological inactivation
- Active drug -> inactive or less active state
- Ex. Phenobarbital -> Hydroxyphenobarbital
Bioactivation/ Toxological activation
- active drug -> active metabolite
- Ex. Codeine -> Morphine
Lethal synthesis
Highly toxic metabolite formed from non-toxic precursor
Pharmacological activation
- inactive drug (pro-drug) -> active metaboliteb
- Ex. Enalapril to enalaprilat
Change of active drug to equally active drug is called
- nothing b/c no change in pharmacological activity
- Ex. Diazepam to Nordiazepam
Change from an active drug to active metabolite with an entirely different pharmacological activity is called
- Change in pharmacological activity
- Ex. Ipronizad to Isoniazid
Primary site for metabolism
Liver
Extra-hepatic metabolism
All tissues have some degree of metabolic activities
Where is the most drug metabolizing activity found?
In SER and cytosol
Microsomal drug metabolizing enzymes
- lipophilic membranes of SER
- Glucuronide conjugation: most important enzyme groups, most oxidative rxns, some reductive and hydrolytic rxns
- Inducible drugs
Non-microsomal drug metabolizing enzymes
- mostly in cytoplasm, mitochondria, bodily fluids
- catalyze few oxidative rxns, some reductive and hydrolytic rxns
- all conjugative rxns; no glucuronidation
- non inducible
2 biotransformation pathways
- Phase I: functionalization (non synthetic/ non conjugative)
- Phase II: conjgation (synthetic)
Phase 1 of Biotransformation
- RIG (from chemistry)
- Hydrolysis
- Oxidation (adding polar functional groups)
- Metabolism
Oxidation
- part of phase I
- polar functional groups added by microsomal enzymes
- mixed function oxidases/ monooxygenases p-450
Conjugation
- phase 2
- combination of drug or phase 1 metabolite w/ endogenous substance -> highly polar product
- Molecular wt. determines route of excretion
How does molecular wt. affect excretion of drugs in phase 2 of biotransformation?
- low wt: excreted in urine
- high wt: excreted via bile (glutathione exclusively, glucuronide mainly)
7 types of conjugation
- glucuronidation
- sulfation
- acetylation
- methylation
- glutathione
- amino acids
- thiosulfate
Glucuronidation
- most common; except for in felines and fish
- conjugation only by haptic microsomal enzymes
- conj. w/ glucuronic acid
Sulfation
- conj. w/ sulfate
- non microsomal enzymes
- IMPORTANT IN FELINES
Acetylation
- conj. w/acetyl group
- drugs w/ amino groups=acetylated
- DOGS AND FOXED DO NOT ACETYLATE
- sulfonamides metabolize via acetylation
Methylation
- conj. w/ methyl groups
- more important for biosynthesis
Glutathione
- ROS: reactive oxide species
- forms mercapturic acid
- tripeptide
- conjugates w/ electrophilic substrates
Amino acids
- glycine
- ornithine in birds
- salicylic acid, nicotinic, and cholic acid
Thiosulfate
- detox. Cyanide
Induction of enzymes
- Severe drugs can induce; especially cytochrome p-450 and glucuronyl transferase
- enhanced metabolism of co-admin. drugs
- ex: carbamazepine, phenobarbital
Inhibition of enzymes
- enzyme degradation or decreased synthesis
- decrease in metabolism of drugs
- ex: erythromycin, clarithromycin, ketoconazole
