Drug Metabolism Flashcards
What is the primary organ involved in drug metabolism?
Liver is quantitatively the most important organ where biotransformation takes place. Other organs have drug metabolizing enzymes.
What the two phases of drug metabolism and what makes them different?
There is Phase 1 and Phase 2 drug metabolism.
In Phase 1, there is a biotransformation of xenobiotics that includes oxidation, hydroxylation and other related changes that introduce or expose a functional group.
In Phase 2, there is also a biotransformation of xenobiotics but this one involves conjugations with a polar head (ex: sulfate or glucuronic acid) yielding a polar metabolite that can be more readily excreted in the bile or urine.
Why is Phase 2 drug metabolism sometimes referred to as conjugation reactions?
This is because these pathways in Phase 2 can be influenced by the availability of the co-substrate (ex: sulfate or activated sulfate).
What are the primary substrates, inhibitors and inducers of CYP3A4?
CYP3A4;
Substrate - midazolam & indinavir
Inhibitor - ritonavir & ketoconazole
Inducer - rifampin & St. John’s Wort
What are the primary substrates, inhibitors and inducers of CYP2D6?
CYP2D6;
Substrate - codeine & fluoxetine
Inhibitor - fluoxetine & quinidine
Inducer - ?? clinical relevance
What are the primary substrates, inhibitors and inducers of CYP2C9?
CYP2C9;
Substrate - S-warfarin & ibuprofen
Inhibitor - fluconazole and amiodarone
Inducer - rifampin & secobarbital
When given a specific CYP450, how can you identify the family, subfamily, individual gene, and allelic variant component? EX: CYP2D6*1A
Family - # after CYP (2)
- families are > 40% amino acid identity
Subfamily - letter after 1st # (D)
- subfamilies are > 55% amino acid identity
Individual gene - # after letter (6)
Allelic variation component - times a letter and a number (*1A)
What is the difference between the mechanism of reversible and irreversible CYP450 inhibition?
Reversible inhibitors of CYP450 compete with substrates for binding at or near the active site of the enzyme. (Nitrogenous compounds that can serve as the sixth axial ligand for iron in the heme are especially potent inhibitors of CYP450)
Irreversible inhibitors are metabolized to reactive species which covalently bind to the heme or binding size residues of the CYP450 protein. The covalent binding renders the CYP450 inoperable and new CYP450 must be synthesized for restoration of normal metabolism.
Why can an enzyme inducer increase the metabolism of drugs metabolized by a DIFFERENT cytochrome P450?
Inducers of drug metabolism enzymes exhibit significant crosstalk meaning they induce the expression of several different families and subfamilies of CYP450 enzymes.
When given a reaction, how can you determine the Phase 2 metabolic process? (ex: sulfation or glucuronidation)
Since Phase 2 metabolism increases the polarity and size of drug molecules, it almost always reduces pharmacologic effect. there are some examples of Phase 2 metabolism serving as an activation process but this is unusual.
Why isn’t genetic variation in metabolism the most important factor in determining variation in drug concentrations and clinical response?
Genetic variation can be important as a determinant of the variability of drug metabolism. Other sources such as diet, other drugs, disease and environmental exposures are often more important than genetic variation.
