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CPR Fall 2019 Test 1 > Lecture 9: biotransformation > Flashcards

Lecture 9: biotransformation Flashcards

1
Q

Drug Biotransformation

A

•The enzymatically-driven process whereby a substance is changed from
one chemical to another

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2
Q

what is the general strategy for eliminating compounds:

A

biotransformation into

more polar, and sometimes larger, derivatives

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3
Q

Consequences of biotransformation

A

1) inactivation (aspirin)
2) active compound to active compound (diazepam->oxazepam)
3) activation (L-dopa)(prodrug)

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4
Q

where does biotransformation mostly occur?

A

Mostly occurs in the liver at some point between absorption into the general
circulation and renal elimination

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5
Q

First-pass effect

A

•The first-pass effect is the process by which oral drugs undergo extensive
biotransformation after absorption prior to entering circulation

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6
Q

what drugs do not undergo first-pass biotransformation?

A

Drugs administered parenterally

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7
Q

phase 1 rxns

A
  • Oxidation, reduction, and hydrolysis
  • catabolic
  • products more reactive, sometimes more toxic
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8
Q

phase II rxns

A

-of enzymes that form a conjugate of the substrate
-Conjugation with endogenous substrates such (e.g., glucuronic acid, sulfuric
acid, acetic acid, or an amino acid) to improve water solubility and increase molecular weight
-anabolic

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9
Q

what are phase 1 rxns carried out by?

A 
mixed function oxidases (MFOs) or
monooxegenases
• Cytochrome P450s (P450 or CYP)
• Flavin-containing monooxygenases (FMO)
• Epoxide hydrolases (mEH, sEH)
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10
Q

where are enzymes for phase I rxns located?

A

lipophilic ER membranes of the liver (and

other tissues)

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11
Q

•Phase II enzymes

A
  • UGT – UDP-glucuronosyltransferase
  • GST – glutathione-S-transferase
  • NAT – N-acetyltransferase
  • TPMT – thiopurine methyltransferase
  • SULT - sulfotransferase
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12
Q

what are genetic factors in biotransformation

A
  • Polymorphisms in xenobiotic-metabolizing enzymes

* Pharmacogenetic differences in enzyme expression levels

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13
Q

nongenetic factors in biotransformation

A
  • Drug-drug interactions
  • Age and sex
  • Circadian rhythm
  • Body temperature
  • Liver size and function
  • Nutritional and environmental factors
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14
Q

what are some compounds that are enzyme inducers

A

phenobarbital, chronic ethanol, aromatic

hydrocarbons such as benzo[a]pyrene (tobacco smoke), rifampin, St. John’s wort

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15
Q

what are compounds that are enzyme inhibitors?

A

grapefruit juice

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16
Q

• Pharmacogenetics

A

the study of differences in drug response due to allelic
variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic
level

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17
Q

• Pharmacogenomics

A

the study of the entire genome to assess multigenetic

determinants of drug response

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18
Q

• Polymorphism

A

a variation in the DNA sequence that is present at an allele

frequency of 1% or greater in a population

19
Q

what does acetaminophen overdosed cause hepatotoxicity?

A
  • overwhelms conjugation pathways
  • glutathione depleted faster than regenerated
  • toxic metabolites accumulate
20
Q

what is the most common disease producing enzyme defect?

A

glucose 6-phosphate dehydrogenase deficiency

  • causes decrease in NADPH and glutathione
  • oxidative stress leads to hemolytic anemia
21
Q

a mutation in what receptor can lead to malignant hyperthermia?

A

ryanodine receptor

-increase in Ca2+ at SR-> muscle contraction

22
Q

what is an ex of a drug that has Variations at multiple gene loci (polygenic effects)?

A
  • Warfarin (Coumadin)
  • Polymorphisms in biotransforming enzymes
  • Polymorphisms in drug target
23
Q

lead compound

A

Defined as a chemical compound that has pharmacological or biological activity and
whose chemical structure is used as a starting point for chemical modifications in order to
improve potency, selectivity, or pharmacokinetic parameters

24
Q

Investigational new drug (IND)

A

is the means by which investigators technically obtain

permission from the FDA to proceed with drug distribution

25
Q

Phase I

A
  • typically first stage in human testing
  • 20-100 subjects
  • is drug safe? pharmacokinetics?
26
Q

phase II

A
  • 100-200 patients
  • does drug work in patients?
  • typically single blind
27
Q

phase III

A

1000-6000 patients

  • does drug work
  • double blind study
  • includes patients with target disease
28
Q

how long does it usually take for a new drug application?

A

8-9 yrs

29
Q

what is phase 4?

A

postmarketing surveillance

30
Q

No-effect dose:

A

the maximum dose at which a specified toxic effect is not seen

31
Q

Minimum lethal dose (LDmin):

A

the smallest dose that is observed to kill any experimental

animal under a defined set of conditions

32
Q

Median lethal dose (LD50):

A

the dose that kills approximately 50% of the animals

33
Q

IRB

A

The purpose of IRB review is to assure that appropriate steps are taken to protect
the rights, safety, and welfare of humans participating as subjects in the research

34
Q

what is the enzyme target of warfarin?

A

vitamin K epoxide reductase (VCORC1)

35
Q

what drugs given when patient has G6PD deficiency are more likely to become ROS?

A
  • sulfur group drugs
  • fava beans
  • infection
  • antimalarial drugs
  • asprin
  • nitrofuantoin
  • NSAIDS
  • qunidine
  • quinine
36
Q

why can we see hyperbilirubinemia in newborns?

A

decrease conjugating activity

37
Q

what does CYP2D6 do

A

convert codeine to morphine

38
Q

what does cyp2C19 do?

A

metabolize acidic drugs

-proton pump inhibitors, antidepressants, antiepileptics, antiplatelet drugs

39
Q

UGT1A1

A
  • conjugates glucuronic acid onto small lipophilic molecules (bilirubin) so it is more readily excreted
  • gilberts syndrome= increase unconjugated bilirubin
40
Q

thiopurine s-methyltransferase (TPMT

A
  • attaches methyl group on aromatic and heterocyclic sulfhydryl compounds
  • pharmacological deactivation of thiopurine drugs
41
Q

OATP1B1 transporter

A
  • on sinusoidal membrane of hepatocytes

- hepatic uptake of mainly weakly acidic drugs and endogenous compound

42
Q

BCRP

A

-efflux transporter in ATP binding cassette superfamily

43
Q

CYP2C9

A

drug metabolizing enzyme that acts primarily on acidic drugs (s-warfarin, phenytoin, NSAIDS)

44
Q

VKORC1

A

target of warfarin

-can have increase sensitivity to warfarin

CPR Fall 2019 Test 1 (8 decks)

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