Svensson Lec 5

Question 1

name the primary organ in drug metabolism

Answer 1

the liver

Question 2

what are the 2 phases of drug metabolism

Answer 2

phase 1 and phase 2

Question 3

what is phase 1 drug metabolism

Answer 3

Biotransformation of xenobiotics that includes oxidation, hydroxylation, and related changes that either introduce or expose a functional group

Question 4

what is phase 2 drug metabolism

Answer 4

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

Question 5

primary substrates for CYP3A4

Answer 5

midazolam, indinavir

Question 6

primary inducers for CYP3A4

Answer 6

rifampin, st. johns wort

Question 7

primary inhibitors for CYP3A4

Answer 7

ritonavir, ketoconazole

Question 8

substrates for CYP2D6

Answer 8

codeine, fluoxetine

Question 9

inhibitors for CYP2D6

Answer 9

fluoxetine, quinidine

Question 10

inducers for CYP2D6

Answer 10

no clinical relevance

Question 11

substrates for CYP2C9

Answer 11

ibuprofen, s-warfarin

Question 12

inducers for CYP2C9

Answer 12

rifampin, secobarbital

Question 13

inhibitors for CYP2C9

Answer 13

fluconazole, amiodarone

Question 14

Given a specific CYP450, identify the subfamily, family, individual gene, and allelic variant.

Answer 14

1. superfamily –> CYP
2. sub family –> first number
3. family –> letter after number
4. gene –> second number
5. allele –> the number&letter after *

Question 15

describe reversible inhibition

Answer 15

–> 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

Question 16

describe irreversible inhibition

Answer 16

• 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

Question 17

Explain why an enzyme inducer may increase the metabolism of the drugs metabolized by different CYP450s.

Answer 17

• It can exhibit cross-talk
  –> Induce expression of several different families and subfamilies of CYP450 enzymes
  –> Can turn on multiple genes toturn on CYPs

Question 18

Provided a reaction, name the phase 2 metabolic process.

Answer 18

• UGT
  –> Chair conformation form
• SULT
  –> Adds a sulfate
• NAT
  –> Adds the double bonded o and methyl

Question 19

Explain why genetic variation in metabolism is often the most important factor in determining variation in drug concentrations

Answer 19

-It can be an important determinant of the variability of drug metabolism,
-So many things contribute and modulate the metabolism of drugs

Question 20

what are the factors determining binding strength in reversible inhibition of CYP450

Answer 20

1. Coordination
   –> Strength with heme iron
2. Hydrophobic
   –> Contacts with site of CYP
3. Specific contacts
   –> Binding site residues