Drug Metabolism: Phase 1

Phase 1 reactions

in vivo chemical modifications that convert the drug to a more polar moiety

Most important enzymes involved in Phase 1 metabolism

Cytochrome P450 enzymes

Flavin monooxygenases (FMOs)

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

esterases, amidases

Cytochrome P450 enzyme

superfamily with the same iron-protoporphyrin IX prosthetic group (heme cofactor) at the catalytic center

transfers an oxygen from the heme cofactor to the drug

Flavin Monooxygenases (FMOs)

involves direct oxidation of nitrogen and sulfur atoms

non-heme, instead use flavin adenine dinucleotide (FAD) prosthetic group

Aromatic hydroxylation

CYP enzyme mediated

usually at the para position

Alkene epoxidation

CYP3A4 mediated epoxide formation

can do a phase 2 reaction - epoxide hydrolase forms a trans diol, which is usually inactive

Fenclofenac

not marketed due to severe liver toxicity

modifications prevent para-hydroxylation

t ½ = 20h

Diclofenac

undergoes para-hydroxylation

t ½ = 2h

benzylic hydroxylation: sites of biotransformation

carbon directly adjacent to the benzylic ring

if the carbon already has a heteroatom (O, N, etc) then oxidation generally does not occur

if there are multiple possible sites, oxidation occurs at the least sterically hindered position

alkyl hydroxylation

occurs generally at omega or omega-1

adds an OH group

Allylic hydroxylation

occurs a carbon over from an allyl group

adds an OH group

oxidative deamination

only occurs in primary alkyl amines

need at least one H on the carbon alpha to the amine

N, O, S dealkylation

hydroxylation followed by fragmentation

typical N-substituents removed are typically methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, and benzyl

amine dealkylation: ring systems

forms a carbinolamine that can break the ring

N-dealkylation of amides

N-oxidation: primary amine

forms a hydroxylamine

can further oxidate to a nitroso group and then form an oxime

N-oxidation: secondary amines

forms a hydroxylamine

can further oxidate to form a nitrone

N-oxidation: tertiary amines

forms an N-oxide

N-oxidation: notes

can also occur on:

pyridines

amides, particularly those of arylamines

Desulfurization

thiocarbonyl to a carbonyl

Sulfoxidation: thioethers

can further oxidize to a sulfone

Sulfoxidation: thiol compounds

forms a sulfenic acid

this can react with another thiol and form a disulfide bridge

Azo reduction

cleaved by azo reductases that are produced by intestinal bacteria

Reduction: arylnitro group

Reduction: carbonyls (Aldo-keto reductases)

Reduction: carbonyls (carbonyl reductases)

Reduction: carbonyls (alcohol dehydrogenase)

Ester hydrolysis

mostly in plasma, some in liver

Amide hydrolysis

peptidase mediated

MAO subtypes

A - placenta, liver, gut

B - brain, liver, platelets

MAO reactions

Amine can be:

primary (2 Hs) or have groups no larger than a methyl

forms an imine intermediate

carbon alpha to the nitrogen cannot be CH3

alcohol and aldehyde oxidations

mediated by dehydrogenase enzymes

Disulfuram

“Antabuse”

used in maintenance of alcohol dependence

inhibits ALDH, increasing acetaldehyde which causes vomiting

Fomepizole

“Antizole”

inhibits ADH, preventing initial biotransformation of compounds, preventing eventual formation of toxic compound in vivo

Tx methanol and ethylene glycol poisoning

Purine oxidations