[LEC] CHAPTER 2 PART 2

Chapter 2 Phase I Drug Metabolism

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