Cytochrome P450 Flashcards
Where is CYP450 primarily located? (Cellular + anatomically)
Liver mt
What enzymes do 90% of Detoxification of drugs?
CYP450 + UGTs
CYP Genetics
CYP450-2D6 Gene
- Poor (2 inactive alleles)
- Intermediate (Heterozygous)
- Extensive (2 Normal Alleles)
- Ultrarapid (Multiple copies)
Define fist pass merabolism
A low systemic availability of the drug as a result of significant metabolism due to GI absorption.
CYP 450 mixed function oxidase system plays major roles in:
- Chol biosynthesis
- Chol conversion to bile acids
- Formation of steroid hormones, androgens, + estrogens
- Metabolism of VitD3
- Omega hydroxylation
- Biotranformation of Xenobiotics
Mechanism of Monooxygenases
Oxidation of NADH/NADPH to Oxygen to create water and add hydroxylate the compound making it more hydrophilic to excrete
CYP450 relation to ETC; Structure
- B-type cytochrome containing protoporphyrin
- Terminal oxidase in ETC
- Planar Fe w/ conserved cysteine residue
Acetominophen + Liver failure
- Most is glucuronidated;
- Small amount is metabolized by CYP3A4 + CYP2E1 into NAPQI -> Hepatotoxicity
Which populations are more at risk for acetaminophen poisoning?
Alcoholics
Tx for NAPQI toxicity
acetylcysteine -> Replenish GSH
Two mechanism of CYP450 induction by other compounds
A. Competitive inhibition of coadministered drugs
Ex. Cimetidine + Ketoconzazole
B. Suicide inhbition: Drug covalently binds heme moeity causing irreversible inhibition of P450.
Chloramp[henicol -> 2B1
Drug classes metabolized by CYP450-3A
- Most CCBs
- Benzodiazapines
- Most Protease inhibitors
- Most HMG-CoA-reductase inhibitors (Statins)
- Ciclosporin
- Non-sedating antihistamines
Inhibitors of CYP450-3A
- Keto/itra/fluconazole
- Cimetidine
- Clarithromycin
- troleandomycin
- grapefruit juice
- Amiodarone
Metabolism by CYP450-2D6
- Codeine
- Many B-Blockers
- Many antidepressants
Inhibitors of CYP450-2D6
- Fluoxetine
- Haloperidol
- Paroxetine
- Quinidine
