Drug Metabolism Flashcards
Why would you want a drug to be lipophilic?
So drugs can access tissues - therapeutic effect
Slide 6 [pic]
Why would you want a drug to be water soluble?
Retained in the blood and delivered to excretion sites
Slide 7 [pic]
We design relativley lipid soluble drugs
Body alters the drug to make it less lipid soluble and easier to excrete.
The process of metaboiksm invovles conversion of drugs (usually quite lipid soluble) to metaboliites (usually less lipid soluble and easeir oto excrete)
Drug metabolism involves two kinds of biochemical reaction
Phase1 - main aim to introduce a reactive grouop tot he drug (increase polarity()
Phase 2 - main aim is to add a water soluble conjugate tot he reactive group
Phase 1 metabolism
Oxidation/reduction creates new functional groups
Hydrolysis unmasks them
NOTE: functional group serves as a point of attachment for phase 2 reactions
Slide 10 [pic]
Most common phase 1 metabolism
Oxidation (often start with hydroxylation)
Mainly in the liver
Different subtypes metabolism different drugs
Cytochrome P450 S.E.R, 57 enzymes
NOTE: levels of enzymes are different in different people
Where does oxidation occur with aspirin?
Slide 12 [pic]
Acetyl group
Nictoine —> cotinine
Oxidation, reduction or hydrolysis?
Slide 13 [pic]
Oxidation
Slide 14 [pic]
Cocaine —> ecgonine methyl ester
Oxidation, reduction or hydrolysis?
Slide 13 [pic]
Hydrolysis
Slide 14 [pic]
chlorla hydrate —> trichloroethanol
oxidation, reduction or hydrolysis?
Slide 13 [pic]
REduction
Slide 14 [pic]
Active parent drug —>
Active parent drug —>
Inactive parent drug —>
Inert metabolite (no effect on body) Active metabolite (prolongs effects) Active metabolite (prodrug - inactive on administration, needs metabolism to activate)
Slide 15 [pic]
Phase 2 metabolism
Adding side chains onto drug Glutathione conjugation Glucuronidation Acetylation Sulfation
Slide 16 [pic]
Most common phase 2 metabolism
Glucuronidation
Glucuronidation is low affinity/high capacity - more likely to occur at high drug dosages
Sulfation
High affinity/low capacity - more likely to occur at low drug dosages
Slide 18+19 [pic]
Glucathione conjugation
Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate
Slide 20 [pic]
How do you convert paracetamol to an electrophile?
Oxidation can mean gaining oxygen or losing hydrogen
Slide 21 [pic]
NOTE: Paracetamol overdose = use up all of GSH conjugate stores. Left with incredibly reactive NAPQI which reacts with proteins in the liver —> massive liver dysfunction (electorphiles are extremely reactive)
Acetylation
Slide 23 [pic]
Methylation
Slide 24 [pic]
Amino acid conjugation
Two reactions possible:
- with carboxylic acid group of AA
- with amino group of AA
Slide 25 [pic]
Importance of drug metabolism
The biological half-life of the chemical is decreased
The duration of exposure is reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
The pharmacology/toxicology of the drug can be governed by its metabolism
