[LEC] CHAPTER 2 PART 2

Chapter 2 Phase I Drug Metabolism

PHASE I REACTIONS

PHASE I REACTIONS

redox reactions (C, O, N, S), oxidative removal, hydrolytic reactions

REDOX REACTIONS

C-redox, N-redox, S-redox

C-REDOX

aromatic hydroxylation, alpha carbon, vinylic/olefinic carbon, benzylic carbon, allylic carbon

C-REDOX: AROMATIC HYDROXYLATION

occurs readily in the presence of ring-activators at the para- position; attaches OH

C-REDOX: ALPHA CARBON

hydroxylated by mixed function oxidases and may undergo immediate oxidation; tend to form lactam metabolites

C-REDOX: VINYLIC/OLEFINIC CARBON

initially forms an epoxide intermediate which is susceptible to enzymatic hydration forming a diol product

C-REDOX: BENZYLIC CARBON

undergoes oxidation as long as it holds a benzylic hydrogen (primary benzylic C - RCOOH; secondary benzylic C - RCOR)

C-REDOX: ALLYLIC CARBON

can also become substrates for hydroxylation

N-REDOX: AROMATIC NITRO AND AZO COMPOUNDS

ar-nitro (NO2) and azo (N=N) compound reduces into 2 Ar-NH2 (aromatic amine)

S-REDOX: S-OXIDATION

oxidized by adding an oxygen then forming the corresponding oxidation product (sulfoxide/sulfone); can also oxidize without oxygen forming disulfide bonds (RSSR’)

OXIDATIVE REMOVAL

dealkylation, deamination, desulfuration, dehalogenation reactions

OXIDATIVE REMOVAL: DEALKYLATION

alkyl group bonded directly to a heteroatom (N, O, S) can be removed by adding a hydroxyl moiety (OH) to the R group (usually an alpha carbon); methyl group removal that results in NH, OH, or SH

OXIDATIVE REMOVAL: DEAMINATION

amine alpha carbon is hydroxylated by monoamine oxidase (MAO) which results to amine cleavage; produced RCOH/RCOR is acted upon by aldo-keto reductase which reduces the substrate to its alcohol counterparts

OXIDATIVE REMOVAL: DESULFURATION

converts C=S bonds to C=O

OXIDATIVE REMOVAL: DEHALOGENATION

halogens are reactive with H2O, which allows addition of OH to the alpha carbon and subsequent cleavage of the halogen atom; results to inactivation of the molecule

HYDROLYSIS

addition of H2O (carried out by hydrolases) to esters and amides results into cleavage and subsequent formation of metabolite (may be active)

AMPHETAMINE

1. c-redox: aromatic hydroxylation

WARFARIN

2. c-redox: aromatic hydroxylation

NICOTINE TO COTININE

1. c-redox: alpha carbon

DIAZEPAM TO 3-HYDROXYDIAZEPAM

2. c-redox: alpha carbon

CARBAMAZEPINE TO CARBAMAZEPINE-10,11-EPOXIDE TO TRANS-10,11-DIHYDROXYCARBAMAZEPINE

c-redox: vinylic/olefinic carbon

TOLBUTAMIDE TO ALCOHOL METABOLITE TO CARBOXYLIC METABOLITE

c-redox: benzylic carbon

QUININE TO 3-HYDROXYQUININE

c-redox: allylic carbon

n-redox: ar-nitro compound

n-redox: ar-azo compound

THIORIDAZINE TO MESORIDAZINE TO SULFORIDAZINE

s-redox: s-oxidation

IMIPRAMINE TO DESIPRAMINE

oxidative removal: N-dealkylation

CODEINE TO MORPHINE

oxidative removal: O-dealkylation

6-(METHYLTHIO) PURINE TO 6-MERCAPTOPURINE

oxidative removal: S-dealkylation

AMPHETAMINE TO PHENYLACETONE

oxidative removal: deamination

THIOPENTAL TO PENTOBARBITAL

oxidative removal: desulfuration

HALOTHANE TO TRIFLUOROACETYL CHLORIDE TO TRIFLUOROACETIC ACID

oxidative removal: dehalogenation

PRODRUG (ENALAPRIL) TO ACTIVE (ENALAPRILAT)

hydrolysis