1-42 Drug Metabolism I Flashcards
Xenobiotics
“strangers to biological systems”, not narual to the body (foods, pharma agents), can reach toxic leavels and drug metabolzing enzymes offer an evolutionary advantage to inactivate and excrete xenobiotics
cometabolism
enzymes present to metabolize endogenous agents also metabolize xenobiotics ex: epinephrine -> MAO, also tyramine -> MAO
why we need drug metabolizing enzymes:
- lipophilic nature of clinically useful agents- poorly excreted, solution: metabolize drugs to make them polar and more easily excreted and less active
Phase 1 / 2 metabolic reaction overview
1: place alluring functional group on drug to make MORE POLAR LESS ACTIVE and provide rnx center for phase 2
- Oxidation (mostly CYPs (cytochrome P450 monooxygenases) ~86%, CYP3A4) (mostly hydroxylations)
- Hydrolysis
2: covalently conjugate the drug at rxn center (provided by phase 1 rnx) making MORE POLAR AND INACTIVE
- Sulfation
- Acetylation
- Glucoronidation: majority of rxns
- Glutathione
- Methylation
Generalized: Drug [phase 1] CYP3A4 [phase 2] glucuronide
CYP450
Most common phase 1 oxidizer in drug metabolism
CYP3A is most prevalent
CYP450 reaction scheme (general)
- cosubstrate: NADPH cytochrom P450 reductase
- needed to supply electrons and H+ to activate the oxygen and hence to provide the raction oxygen species essential for complete reation to occur
- heme ring binds Fe and is used as oxidizer
- end goal of reactions: one atome of oxygen from O2 is added t othe drug to form a hydroxylated drug and the other oxygen is converted into water
Phase 1 drug metabolism types (CYP450 depedent oxidations)
- hydroxylation
- aromatic hydroxylation
- Sulfur oxidation
- Nitrogen oxidation
- Oxidative dealkylation
- Nitrogen dealkylation
- Oxygen dealkylation
CYP3A4 responsible for 55-60% of phase 1 rxns
Phase 1 drug metabolism types (CYP independent)
- Oxidations
- via dehydrogenases (important example, ethanol metabolism via alchohol dehydrogenase then via aldehyde dehydrogenase with NAD+ as Hydrogen acceptor)
- via amine oxidases: oxidative deamination (replace NH2 with o=C-H)
PHase 1 reactions- Hydrolysis
- ester hydrolysis (O=C=O-x) via ESTERASES
- Epoxides (cancer causing DNA damager) to diols (less reactive safer) via EPOXIDE HYDROLASES
Phase 2 drug metabolism reaction types
- **Sulfation: via SULFOTRANSFERASES, cytosolic enzymes require PAPS to be activated, adds SO3H to an OH replacing the H
- Albuterol and *Acetominophen* are “prelubbed” with a OH group so they dont require phase 1 metabolism and are just ready for Sulfation
- Acteylation: via N-ACETYL TRANSFERASES (NATs), cytosolic, require Acetyl CoA, makes drugs LESS polar, adds O=C-CH3
- **Glucuronidation: via UDP GLUCURYONYL TRANSFERASES (UGTs), in the smooth ER and require UDP glucuronic acid
- all benzos inactivated by glucuronide conjugation
- all drugs expect MORPHINE inactivated by this
- **Acetominophen** metabolized to non-toxic excrete
- **Glutathione: via Glutathione S Transferases, transferred to toxic metabolites (electrohpiles) to protect against toxicity,
- prevent cancers from developing
- BUT once cancers develop, high levels of GST in many tumor types cause increased cell prolieation and a resistance to cancer chemo
- **Acetominophen** glutathione conjucation can resuce this drug from a toxic metabolite
- Methylation: via METHYLTRANSFERASES, cytosolic, methyl group transferred to aromatic rings with N, O, S, S-adenosylmethionine is methyl donor
**Know for Exam**
Polymorphisms in CYPs
CYP2D6: important CYP responsible for genetic polymorphisms, many CNS drugs use, codeine, metoprolol, tricyclic antidepressants
CYP2C9: celecoxib, ibuprofen, S-warfarin
CYP2C19: diazepam, omeprazole, propranolol
CYP1A2: caffeine, theophyline
CYP2E1: acetaminophen, ethanol
ALL OTHERS GO THROUGH CYP3A4 (pretty much)
