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Medicinal Chemistry > Drug Metabolism Pt 8: Notes III > Flashcards

Drug Metabolism Pt 8: Notes III Flashcards

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1
Q

PHASE II REACTIONS
• They are ______.
• They are fast compared to Phase I, so phase I reactions are considered the rate limiting step.
• There are lots more Phase II metabolites in the blood.

A

conjugation reactions

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2
Q

Glucuronidation
• Drug attacks the anomeric carbon of glucuronide, making it more polar to aid in excretion. It is a nucleophilic attack by SN@ reaction, thus stereochemistry changes.
• This reaction can be done by drugs with ??

There are 19 different isoforms of glucuronides for specificity.

A

OH, SH, NH2, COO groups.
• Enzyme: UDP glucuronyl transferase
•

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3
Q

Sulfate formation

  • Done by the enzyme ____.
  • There are _____ of this enzyme.
  • Works on _____, ____, primary and secondary amines.
A
  • sulfonyl transferase
  • 11 isoforms
  • phenols, alcohols
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4
Q

Glutathione conjugation

  • Mainly done for detoxification.
  • Glutathione is a tripeptide structure: _________ with the sulfhydryl group that is the nucleophile that attacks the electrophile.
A
  • gamma-glutamyl-cystemyl-glycine
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5
Q

Glutathione conjugation

• In arene oxides, glutathione attacks the epoxide and gets attached in the para position. A molecule of water is lost and the molecule is detoxified.

  • Glutathione conjugate is _____.
  • Glutathione undergoes _______, converting it to mercapturic acid.
A
  • not excreted, but it is recycled
  • peptide cleavage and acetylation
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6
Q

Give example of Glutathione conjugation.

A

E.g.: Acetaminophen -> toxic p-Quinone imine -> mercapturic acid by GSH.

The mechanism is called Michael addition. KNOW MECHANISM!

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7
Q

Michael addition. KNOW MECHANISM!

A
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8
Q

FACTORS AFFECTING DRUG METABOLISM

Factors that affect drug metabolism are quantitative rather than qualitative.

Think about factors as clogging the different pipes through which drug is metabolized.

Depending on the amount of metabolite we get because of the pathways that are blocked, drug metabolites can increase or decrease.
- Metabolic shunting: planned or unplanned termination of an enzyme that changes the concentration of the metabolism. It occurs when one enzyme reaction is saturated so that it foes through another enzyme mechanism.

Metabolic shunting can lead to drug interactions, increased toxicity or prolonged activity.

A
  • If metabolism is increased, the concentration of drug is decreased.
  • If metabolism is decreased, the concentration of drug is increased. Each of these has its own consequences depending on the drug.
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9
Q

Cytochrome P450 Multiplicity

  • These enzymes have > 1000 genes, some of which are pseudogenes.
  • In humans, there are 57 distinct P450s in 17 families found largely in our liver.
A
  • It is thought that P450s evolved from endogenous P450s that handled endogenous molecules like fatty acids, steroids. They evolved to degrade xenobiotics.
  • P450 enzymes have a heme center and a unique active site.
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10
Q

Cytochrome P450 Multiplicity

Nomenclature: CYP2D6:CYP = cytochrome P450, 2: family number, D: subfamily, 6: individual form
• The lower end CYPs (1-3) deal with small molecules like drugs. The larger number CYPs (4-21) deal with fatty acids, steroids, bile acids

A

Important CYPs for drugs:

2C9, 2D6, 2E1, (3A4, 3A5). 2E1 metabolizes acetaminophen, ethanol.

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11
Q

FACTORS
Age Very young: not fully metabolically competent. E.g. cholarmphenicol toxicity in new borns that happens because of poor glucuronidation since babies virtually has no phase II enzymes. Leads to Gray baby syndrome.
Elderly: the elderly have diminished metabolism and excretion and diminished enzyme induction. They also take more drugs, so drug interactions can be severe. Nowadays, dosage in the elderly is from low to high.

A

The Beer’s list contains medications that are not properly
metabolized in the elderly.

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12
Q

Disease

  • Liver disease: drug is not cleared by the liver’s first pass effect. This can lead to overdose.
  • Kidney damage: _________
A

drug metabolites might get recycled -> liver damage

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13
Q

Species differences
- There can be intra- and interspecies variation.

A

E.g. cats form sulfates and pigs form glucuronides only. Rats have 6 CYP2D isoforms but humans have only 1 CYP2D isoform. Thus they are not ideal models for human medications.

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14
Q

Gender

A
  • Drugs that are gender specific like oral contraceptives are only known for that specific gender.
  • The difference in metabolism is probably hormonal based.
  • N demethylation of erythromycin works in females better
  • Propanolol oxidation works in males better.
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15
Q

Pregnancy
- Concern for fetus

A
  • Placenta has an increased CYP1A in a smoker mother. This leads to teratogenicity, carcinogenicity, hepatoxicity in the fetus.
  • During pregnancy, there can be a profound induction of enzymes that metabolize drugs so the dosage might have to be increased.
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16
Q

Environmental factors like smoking

A

Cigarette smoke contain PAH (polycyclic aromatic hydrocarbons) that induce CYP1A2. The enzyme metabolizes PAH to carcinogens that increase the risk for lung and colon cancer.

17
Q

Drug dose
Maintaining the dosage of the drug without making it toxic is essential while considering drug
metabolism.

A

E.g. acetaminophen can be metabolized by glutathione, sulfate formation and P450.

It doesn’t become toxic until all the GSH runs out and there is none left to convert p-quinoneimine to mercapturic acid.

18
Q

Enzyme induction:

  • This process takes place in the gene level. Enzyme induction happens as a result of adaption by the liver based on the exposure to the drug. The liver regulates the genes coding for the enzymes.
  • The drug acts as the inducer that binds to the repressor protein and pulls of the repressor, allowing gene expression through transcription. Thus, induction causes more enzymes to be present.
A
  • Induction can also be done post transcriptionally, by methylating mRNA to stabilize it so that it is present longer -> more proteins are made -> increase in enzyme.
  • Stopping induction can lead to toxicity by the build-up of metabolites, or by the increased amount of drug in the system. Induction can be prevented by herbal medicines and other drugs.
  • There are special P450 isozymes that are inducible: 3A4, 2E1(ethanol), 2D6 (not inducible/moderately inducible)
19
Q

Enzyme inhibition

  • Inhibition occurs at the enzyme level. It is ______ induction.

Inhibition can lead to prodrugs not being converted to _____-, ____, _____.

  • Virtually any enzyme involved in metabolism can be inhibited.
  • 3A4 and 2D6 inhibitions affect a ____ number of drugs.
A
  • NOT the opposite of
  • active form, drug interactions, toxic effects.
  • large
20
Q

Diet: e.g. grapejuice inhibits 3A4 that prevents seldane to go to ____ antihistamine.

A

active

21
Q

Heredity:

  • Genetic polymorphism: demonstrably different forms or levels of enzymes in distinct population. Incidence: >1% of population.
  • Poor metabolizers ~ ____
  • Fast metabolizers ~ _________
  • Differences in heredity can be individual or interracial differences
A
  • toxicity
  • therapeutic failure
22
Q

Define Pharmacogenomics

A
  • It is defined by the influence of DNA sequence variation on drug response
  • There can be a variation in the enzymes, drug transport, drug targets.
  • These variations can bring out adverse effects, therapeutic failures, drug interactions.
23
Q

Pharmacogenomics

o CYP2D6- normal enzyme
o CYP2D6*4: _____ _____- inactive enzyme
o CYP2D6*5: gene deletion- no enzyme
o CYP2D6*2xn: gene duplication-twice ____ _____
o CYP2D6*17: 3 bases- decrease enzyme ____

A
  • defective splicing
  • more active
  • affinity
24
Q

Phenotypic populations

A

o Poor metabolizers
o Intermediate metabolizers
o Extensive metabolizers
o Ultrarapid metabolizers

25
Q

Marker probe: _________

A

measures substrate/product.

26
Q

The extreme left of the graph is ultrarapid metabolizers. The extreme right of the graph is poor metabolizers

A
27
Q

CYP2D6

Genetic Polymorphism: 80 different alleles

Also gene duplication (1-13 copies)

Many possibilities:

1-4

A
  1. Normal enzyme (fully functional, normal amounts
  2. Normal enzyme in diminished amounts
  3. Poorly active or inactive enzyme
  4. Massive amounts of enzyme
28
Q

CYP2C19

Interracial differences:

3% Caucasians (European) —PM’s

13-23% SE-Asian descent –PM’s

Metabolizes _____

Consequences: _____

A
  • S-Mephenytoin
  • Sedation
29
Q

CYP2D6

Interracial Differences

5-10% Caucasians (European) —PM’s

1-2% SE-Asian descent –PM’s

Potential consequences ?

A
  • PM’s toxicity
  • UM’s failure
  • Prodrugs ? (consider codeine to morphine bioconversion for each group
30
Q

Azothioprine (antileukemia drug)

Autosomal codominant intheritance (TPMT-H/TPMT-H)

If _____ _____ no activity

Low TPMT—> fatal myelosupression

A
  • homozygous recessive/ 1% Caucasians

Medicinal Chemistry (8 decks)

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