Svensson Lec 5 Flashcards
name the primary organ in drug metabolism
the liver
what are the 2 phases of drug metabolism
phase 1 and phase 2
what is phase 1 drug metabolism
Biotransformation of xenobiotics that includes oxidation, hydroxylation, and related changes that either introduce or expose a functional group
what is phase 2 drug metabolism
Biotransformation of xenobiotics that involves conjugation with a polar group yielding a polar metabolite that can be more readily excreted in the bile or urine
–>Sometimes referred to as conjugation reactions and can be influenced b the availability of the co-substrate
primary substrates for CYP3A4
midazolam, indinavir
primary inducers for CYP3A4
rifampin, st. johns wort
primary inhibitors for CYP3A4
ritonavir, ketoconazole
substrates for CYP2D6
codeine, fluoxetine
inhibitors for CYP2D6
fluoxetine, quinidine
inducers for CYP2D6
no clinical relevance
substrates for CYP2C9
ibuprofen, s-warfarin
inducers for CYP2C9
rifampin, secobarbital
inhibitors for CYP2C9
fluconazole, amiodarone
Given a specific CYP450, identify the subfamily, family, individual gene, and allelic variant.
- superfamily –> CYP
- sub family –> first number
- family –> letter after number
- gene –> second number
- allele –> the number&letter after *
describe reversible inhibition
–> Similar to receptor antagonist
- Nitrogenous compounds that can serve as the sith axial ligand for iron in the heme are especially potent inhibitors of CYP450
–> Stronger affinity
- Additional hydrophobic contacts stabilize ligand-protein binding
describe irreversible inhibition
- Mechanism-based inhibition
- Metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues in the binding site
- further metabolism of same or other drug is delayed as CYP needs to be resynthesized so it has the longest lasting inhibition
Explain why an enzyme inducer may increase the metabolism of the drugs metabolized by different CYP450s.
- It can exhibit cross-talk
–> Induce expression of several different families and subfamilies of CYP450 enzymes
–> Can turn on multiple genes toturn on CYPs
Provided a reaction, name the phase 2 metabolic process.
- UGT
–> Chair conformation form - SULT
–> Adds a sulfate - NAT
–> Adds the double bonded o and methyl
Explain why genetic variation in metabolism is often the most important factor in determining variation in drug concentrations
-It can be an important determinant of the variability of drug metabolism,
-So many things contribute and modulate the metabolism of drugs
what are the factors determining binding strength in reversible inhibition of CYP450
- Coordination
–> Strength with heme iron - Hydrophobic
–> Contacts with site of CYP - Specific contacts
–> Binding site residues
