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Pharm Exam 1 > Kocarek - Drug Metabolism > Flashcards

Kocarek - Drug Metabolism Flashcards

1
Q

Drug Metabolism

A

Chemical alteration of xenobiotics in the body. Converts lipophilic chemicals into hydrophilic chemicals that are readily excreted in urine or bile.

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2
Q

Xenobiotic

A

Any compound normally foreign to living systems

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3
Q

Issues of drug metabolism (4)

A
  1. Genetics
  2. metabolism-dependent toxicity
  3. Drug-drug interactions
  4. Pathophysiological conditions
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4
Q

When does acetaminophen become toxic?

A

When the dose overwhelms the glucuronidation and sulfation pathways and forms NAPQI via the cytochrome P450 path (mainly CYP2E1 and CYP3A4)

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5
Q

How can NAPQI be detoxified?

A

glutathione conjugation

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6
Q

What does MPTP do to the body?

A

Metabolism dependent.

It crosses the BBB and is metabolized by MAO to MPDP+ that then auto-oxidizes to MPP+. This concentrates in DA neurons where it impairs mitochondrial respiration.

Creates a Parkinson’s Disease-like condition

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7
Q

What does grapefruit juice inhibit?

Due to what chemical?

A

CYP3A4

Due to furanocoumarins

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8
Q

How is terfenadine cardiotoxic?

A

drug-drug interaction involving CYP3A4. CYP3A4 converts the prodrug terfenadine to fexofenadine in the intestine and liver. A CYP3A4 inhibitor, ketoconazole or erythromycin, causes terfenadine to accumulate to cardiotoxic levels

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9
Q

How can metabolism be affected by pathophysiological conditions

A

Hepatic metabolism may be compromised in liver disease

Cardiac disease can reduce blood flow to liver, reducing metabolism of flow-limited drugs

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10
Q

Four categories of biotransformation reactions

A
  1. Oxidation - P1
  2. Reduction - P1
  3. Hydrolysis - P1
  4. Conjugation - P2
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11
Q

Two major categories of biotransformation reactions

A

Phase I: oxidation, reduction or hydrolysis reactions

  • Convert parent compound to more polar metabolite
  • May make the compound more readily excreted
  • May reveal a functional group that can serve as a site for additional metabolism

Phase II: conjugation of a small, endogenous substrate molecule with functional groups already present on drug or added/revealed by phase I metabolism

Important Point: either one of the above phases may occur first

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12
Q

How is procaine metabolized?

A

Hydrolysis of the ester linkage, which exposes a carboxylic acid group

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13
Q

Phase III metabolism

A

Describes the transporter proteins that pump xenobiotics or conjugates out of cells.

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14
Q

How is isoniazid metabolized? What product is hepatotoxic?

A

Undergoes phase II first: conjugated by acetylation (II) then the acetylated metabolite is then hydrolyzed (I) to produce isonicotinic acid and acetylhydrazine.

acetylhydrazine is hepatotoxic

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15
Q

What enzymes catalyze >50% of orally effective drugs in current use?

A

CYP2D6 and CYP3A4

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16
Q

What reactions are catalyzed by enzymes that participate in intermediary metabolism?

A

Cinnamic acid to benzene by mitochondrial fatty acid beta-oxidation enzymes

anti-HIV drug zidovudine to a triphosphate nucleoside by enzymes in the salvage pathway

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17
Q

Xenobiotic sensing receptors

A

Aryl hydrocarbon (Ah) receptor
Pregnane X receptor (PXR)
Constitutive androstane receptor (CAR)

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18
Q

Aryl hydrocarbon (Ah) receptor ligands:

A

prototype ligands are aromatic hydrocarbons and polychlorinated hydrocarbons

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19
Q

Regnane X receptor (PXR) ligands:

A

Ligands include a large number of drugs and other xenobiotics (ex rifampicin and hyperforin)

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20
Q

Constitutive androstane receptor (CAR) activated by:

A

Activiated by phenobarbital and many other drugs and xenobiotics

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21
Q

How is codine converted to morphine?

A

Phase I reaction (O-demethylation) catalyzed by CYP2D6)

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22
Q

Where is the highest level of CYPs found?

A

endoplasmic reticulum (microsomes) of liver, but are also present in virtually all cells

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23
Q

Cytochrome P450 is involved in what type of metabolism?

A

Phase I oxidation

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24
Q

of Human CYPs

A

57
18 families
708 gene families

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25
Q

Overall P450 rxn

A

Drug + NADPH + O2 –>Oxidized Drug + NADP+ + H2O

Incorporates an atom of oxygen into the substrate

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26
Q

CYP1

A

aromatic hydrocarbons

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27
Q

CYP2

A

phenobarbital, “phenobarbital-like” compounds

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28
Q

CYP3

A

Steroids, phenobarbital, “phenobarbital-like” compounds

29
Q

CYP4

A

Peroxisome proliferators

30
Q

How close are CYPs in the same family?

A

CYPs in the same family have at least 40% amino acid similarity

31
Q

Cytochrome P450 catalytic cycle

A

o Drug adds first to cytochrome P450 (Fe3+)
o Addition of electron from NADPH (Fe2+)
o Addition of O2 (Fe2+−O)
o Addition of another electron from NADPH (Fe2+−O2(-))
o Addition of 2 protons (H+) and release of water (Fe3+−O)
o Transfer of O to drug and release of hydoxylated drug (d-OH) –> regeneration of P450 (Fe3+)

32
Q

Componenets required for the P450 system

A

o NADPH
o NADPH-cytochrome P450 reductase (flavoprotein)
o Cytochrome P450
o Lipid environment

33
Q

Types of oxidative reactions

A

Hydroxylation of an aliphatic or aromatic carbon

epoxidation of a double bond

heteroatom (O,S, and N) dealkylation

heteroatom (S,N, I) oxygenation and N-hydroxylation

oxidative group transfer

cleavage of esters

dehydrogenation

34
Q

Example of Hydroxylation of an aliphatic carbon

A

tolbutamide to hydroxytolbutamide (via CYP2C9)

35
Q

Example of Hydroxylation of an aromatic carbon

A

(S)-Mephenytoin to 4’-Hydroxy-(S)-Mephenytoin (via CYP2C19)

36
Q

Example of an expoxidation

A

Carbamazepine (anticonvulsant) to carbamazepine-10,11-epoxide (stable)

and

Carbamazepine to carbamazepine-2,3-epoxide (unstable arene oxide)

37
Q

Example of heteroatom oxygenation

A

S: omeprazole –>
N: NNK –> NNK N-oxide

38
Q

Example of heteroatom dealkylation

A

Codeine to morphine via (CYP2D6): an example of O-dealkylation

39
Q

Other oxidatative enzymes (10)

A 
flavin monooxygenase
alcohol dehydrogenase
aldehyde dehydrogenase
aldehyde oxidase
xanthine oxidoreductase
monoamine oxidases
diamine oxidases
polyamine oxidase
semicarbazide-sense. amine oxidase
peroxidase
40
Q

Reduction: 3 types

A

Azo/nitro
Carbonyl
Quinone

41
Q

Azo and nitro reduction

catalyzed by:

A

Catalyzed by intestinal microflora

sometimes by P450

42
Q

Example of azo reaction

A

prontosil to 1,2,4-triaminobenzene and sulfanilamide (first sulfa drug)

43
Q

Carbonyl reduction:

catalyzed by what?

A

Reduction of aldehydes to primary alcohols

and

ketones to secondary alcohols

catalyzed by NAD(P)H-dependent reductase

44
Q

Two superfamilies of NAD(P)H-dependent reductase

A
  1. Aldo-ketoreductase

2. Short-chain dehydrogenases

45
Q

Quinones can be reduced to hydroquinones by:

A

Quinones can be reduced to hydroquinones by NAD(P)H-quinone oxidoreductase-1 (NQO1,DT-diaphorase) and NQO2

46
Q

What does hydrolysis cleave?

A

esters, amides, thioesters, phosphoric acid esters, acid anhydrides, and lactones

47
Q

What enzymes hydrolyze xenobiotics?

A

Carboxylesterases (CE) and Epoxide hydrolases (main ones)

Cholinesterases (AChE, butyrylcholinesterase)
Paraoxonases (lactonases)
Alkaline phosphase
Peptidase

48
Q

What do CE1 and CE2 hydrolyze?

A

xenobiotic esters and amides

ex: procaine by CE2

49
Q

What are the 2 (of 5 total) epoxide hydrolases that function in xenobiotic metabolism?

A

Microsomal epoxide hydrolase (mEH)

Soluble epoxide hydrolase (sEH)

50
Q

How do epoxide hydrolases work?

what are the products?

A

catalyze the trans-addition of water to alkene epoxides and arene oxides

Products are trans-1,2-dihydrodiols

51
Q

What type of cell expresses mEH and sEH?

A

Generally, the same type of cell that expresses cytochromes P450

52
Q

How can EH play a role in bioactivation?

A

polycyclic aromatic hydrocarbon “bay-regions” diolepoxides

Bay region epoxides are resistant to hydrolyation by EH, resulting from steric hindrance from the nearby dihydrodiol group

53
Q

Conjugation reaction

A

xenobiotic (or endogenous substrate) is coupled with an endogenous molecule

54
Q

How do the conjugated metabolites compare with substrate?

A

More polar

pharmcologiaclly inactive

more readily excreted

(Not always the case)

55
Q

Major conjugation reactions

A 
Glucuronidation*
Sulfation (sulfonation)*
Glutathione conjugation*
Acetylation* (GGAS)
Methylation
Amino acid conjugation
56
Q

Glucuronidation mechanism

A

transfer of glucuronic acid from the co-factor UDP-glucuronic acid to a nucleophilic heteroatom on a substrate

57
Q

Glucuronidation substrates

A

aliphatic alcohols, phenols, carboxylic acids, amines, sulfhydryl groups

58
Q

Glucuronidation is catalyzed by:

A

Uridine 5’-diphosphate (UDP)-glucuronosyltransferases (UGTs)

59
Q

How many UGTs are encoded by the UGT1 locus? UGT2?

What are UGTs localized to?

A

UGT1: 9 (have different exon 1s)
UGT2: 10

localized to microsomes

60
Q

How is morphine converted into an active metabolite?

A

UGT2B7 adds glucuronic acid to the 6-position of morphine

61
Q

Sulfation (sulfonation) mechanism

A

transfer a sulfonate group from the co-factor 3-phosphoadenosine-5’-phosphosulfate (PAPS) to an available group on a substrate

62
Q

Substrate of sulfation

A

aliphatic alcohols, phenols, amines, N-oxides, N-hydroxyls

Not carboxylic acids

63
Q

Sulfation is catalyzed by:

How many are there?

A

SULTS

14 human SULTs

64
Q

Example of sulfation rxn:

A

17 beta-estradiol to Estradiol-3-sulfate via SULT1E1

65
Q

Glutathione conjugation mechanism

A

transfer of a glutathione (Glu-Cys-Gly) group to an electrophilic atom

66
Q

Glutathione substrates

A

epoxides, arene oxides, nitro groups, hydroxylamines

67
Q

Glutathione is catalyzed by:

How many are there?

A

Glutathione transferases (GSTs)

24human GSTs

Cytosolic, microsomal, mitochondrial enzymes

68
Q

Acetylation

Mechanism:
Substrates:
Catalyzed by:

A

Phase II metabolism

Transfers acetyl group from co-factor acetyl coenzyme A to an amino group on a substrate

Substrates are amines

Catalyzed by N-acetyltransferases
NAT1 and NAT2 are located in cytosol

69
Q

Methylation

Mechanism:
Substrates:
Catalyzed by:

A

Phase II metabolism

Transfers a methyl group from the cofactor S-adenosylmethionine (SAM)to an electron-rich heteroatom (O, N, or S) on a substrate; C-methylation is possible but rare

Substrates: phenols, catechols, aliphatic and aromatic amines, N-heterocyclic compounds, and sulfhydryl-containing compounds; certain metals can also be methylated (inorganic mercury, arsenic, selenium)

usually decreases the water solubility of xenobiotics (exception: N-methylation of pyridine-containing compounds, which produces quaternary ammonium ions, and S-methylation of thioethers which produces positively charged sulfonium ions)

Catalyzed by methyltransferases: COMT, POMT, PNMT, HNMT, NNMT, and others

Pharm Exam 1 (23 decks)

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