Drug Metabolism: Phase 1

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35 Terms

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Phase 1 reactions

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

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Most important enzymes involved in Phase 1 metabolism

Cytochrome P450 enzymes

Flavin monooxygenases (FMOs)

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)

esterases, amidases

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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

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Flavin Monooxygenases (FMOs)

involves direct oxidation of nitrogen and sulfur atoms

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

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Aromatic hydroxylation

CYP enzyme mediated

usually at the para position

<p>CYP enzyme mediated</p><p>usually at the para position</p>
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Alkene epoxidation

CYP3A4 mediated epoxide formation

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

<p>CYP3A4 mediated epoxide formation </p><p>can do a phase 2 reaction - epoxide hydrolase forms a trans diol, which is usually inactive</p>
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Fenclofenac

not marketed due to severe liver toxicity

modifications prevent para-hydroxylation

t ½ = 20h

<p>not marketed due to severe liver toxicity</p><p>modifications prevent para-hydroxylation</p><p>t ½ = 20h</p>
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Diclofenac

undergoes para-hydroxylation

t ½ = 2h

<p>undergoes para-hydroxylation</p><p>t ½ = 2h</p>
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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

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alkyl hydroxylation

occurs generally at omega or omega-1

adds an OH group

<p>occurs generally at omega or omega-1</p><p>adds an OH group</p>
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Allylic hydroxylation

occurs a carbon over from an allyl group

adds an OH group

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oxidative deamination

only occurs in primary alkyl amines

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

<p>only occurs in primary alkyl amines</p><p>need at least one H on the carbon alpha to the amine</p>
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N, O, S dealkylation

hydroxylation followed by fragmentation

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

<p>hydroxylation followed by fragmentation</p><p>typical N-substituents removed are typically methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, and benzyl</p>
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amine dealkylation: ring systems

forms a carbinolamine that can break the ring

<p>forms a carbinolamine that can break the ring</p>
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N-dealkylation of amides

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N-oxidation: primary amine

forms a hydroxylamine

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

<p>forms a hydroxylamine</p><p>can further oxidate to a nitroso group and then form an oxime</p>
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N-oxidation: secondary amines

forms a hydroxylamine

can further oxidate to form a nitrone

<p>forms a hydroxylamine</p><p>can further oxidate to form a nitrone</p>
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N-oxidation: tertiary amines

forms an N-oxide

<p>forms an N-oxide</p>
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N-oxidation: notes

can also occur on:

pyridines

amides, particularly those of arylamines

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Desulfurization

thiocarbonyl to a carbonyl

<p>thiocarbonyl to a carbonyl</p>
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Sulfoxidation: thioethers

can further oxidize to a sulfone

<p>can further oxidize to a sulfone</p>
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Sulfoxidation: thiol compounds

forms a sulfenic acid

this can react with another thiol and form a disulfide bridge

<p>forms a sulfenic acid</p><p>this can react with another thiol and form a disulfide bridge</p>
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Azo reduction

cleaved by azo reductases that are produced by intestinal bacteria

<p>cleaved by azo reductases that are produced by intestinal bacteria</p>
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Reduction: arylnitro group

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Reduction: carbonyls (Aldo-keto reductases)

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Reduction: carbonyls (carbonyl reductases)

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Reduction: carbonyls (alcohol dehydrogenase)

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Ester hydrolysis

mostly in plasma, some in liver

<p>mostly in plasma, some in liver</p>
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Amide hydrolysis

peptidase mediated

<p>peptidase mediated</p>
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MAO subtypes

A - placenta, liver, gut

B - brain, liver, platelets

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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

<p>Amine can be:</p><p>primary (2 Hs) or have groups no larger than a methyl  </p><p>forms an imine intermediate</p><p>carbon alpha to the nitrogen cannot be CH3</p>
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alcohol and aldehyde oxidations

mediated by dehydrogenase enzymes

<p>mediated by dehydrogenase enzymes</p>
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Disulfuram

“Antabuse”

used in maintenance of alcohol dependence

inhibits ALDH, increasing acetaldehyde which causes vomiting

<p>“Antabuse”</p><p>used in maintenance of alcohol dependence</p><p>inhibits ALDH, increasing acetaldehyde which causes vomiting</p>
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Fomepizole

“Antizole”

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

Tx methanol and ethylene glycol poisoning

<p>“Antizole”</p><p>inhibits ADH, preventing initial biotransformation of compounds, preventing eventual formation of toxic compound in vivo</p><p>Tx methanol and ethylene glycol poisoning</p>
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Purine oxidations

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