Phase I and Phase II Metabolism

Question 1

Aliphatic hydroxylation

Answer 1

OH attachment on penultimate carbon on aliphatic chain (or a C directly attached to aromatic group)

Question 2

Aromatic hydroxylation

Answer 2

OH added to an aromatic ring
EDG increase hydroxylation; EWG decrease hydroxylation
Adds in para position
Eliminate hydroxylation by adding EWG to para

Question 3

N or S oxidation

Answer 3

S more common

RSCH3 –> RSOCH3

Question 4

N, O, or S dealkylation

Answer 4

ROCH3 –> ROCH(OH)CH3 –> R-OH + CH2OCH3

Question 5

Deamination

Answer 5

R-CH2NH2 –> (with MAO) RCH(OH)NH2 –> RCH2O + NH3

Question 6

Nitrate reduction

Answer 6

RCH2NO2 –> RCH2NH2

Question 7

Oxidative dehalogenation

Answer 7

RCH2X –> RCH(OH)X –> RCHO

Question 8

Esterase action

Answer 8

RCOOR + H2O –> RCOOH + ROH

Question 9

Amidase action

Answer 9

RCONHR + H2O –> RCOOH + R-NH2

Question 10

Glucuronide conjugation

Answer 10

enzyme = UDP-glucuronosyltransferase (UGT)
ligand = UDP glucuronic acid (UDP-GA)
target functional groups: OH, SH, NH, COOH, R-NH-OH, R-S-OH
if product 350Da - feces

Question 11

Glutathione conjugation

Answer 11

Enz = glutathione S transferase (GST)
ligand = gamma-glutamyl-cystenyl-glycine (GSH)
target = any electrophile, carbonyls, substituted aromatic rings, double bonds
excreted in feces
Drug –> Drug-S-R

Question 12

sulfate conjugation

Answer 12

enz = sulfotransferase (ST)
ligand = phosphoadenosine phosphosulfate (PAPS)
Target = phenols, OH, catechols, hydroxyamines, hydroxysteroids (estradiols)
excreted in urine
Drug –> Drug-SO4-

Question 13

Methylation

Answer 13

enz = methyltransferase (MTase)
ligand = S-adenosyl methionine (SAM)
target = O, N, S
excreted in urine or feces
Drug --> Drug-O-CH3

Question 14

acetylation

Answer 14

enz = acetyl transferase (AT) --> could be N,O, or S acetyl transferase (N is most important)
ligand - acetyl co-enzyme A (acetyl CoA)
target = N, sometimes O and S
excreted in urine
Drug --> Drug-COCH3

Question 15

AA conjugation

Answer 15

Enz = aminoacyl transferase (AA-T)
ligand = drug-CoA
target = COOH
mostly excreted in urine