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elimination and detox wk 1 > biotransformation - pt 1 > Flashcards

biotransformation - pt 1 Flashcards

1
Q

what is biotransformation

A

enzymatic changes made to a substance

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2
Q

what is a phase I reaction

A

oxidation - CYP450

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3
Q

what is a phase II reaction

A
  • glucuronidation/glucosidation
  • acetylation
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4
Q

most metabolic products are:

A

pharmacologically LESS active

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5
Q

what is a prodrug

A

the metabolite is MORE active than the substance administered

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6
Q

what are examples of prodrugs

A
  • cefpodoxime proxetil
  • erythromycin-ethylsuccinate
  • codeine
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7
Q

what are the two types of oxidative reactions

A
  • oxygen is incorporated into the drug molecule (addition of ‘-OH’)
  • oxidation causes the loss of part of the drug molecule
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8
Q

what is cytochrome P450

A
  • mixed function oxidases or monooxygenases
  • present mostly in the microsomes, some also in mitochondria
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9
Q

what does drug oxidation require

A

CYP450 (enzyme); NADPH-CYP450 reductase (enzyme); NADPH (cofactor); and O2 (cofactor)

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10
Q

what are the 4 steps of oxidation via CYP450

A
  1. oxidized CYP450 combines with a drug substrate to form complex
  2. NADPH donates 2 electrons to NADPH-CYP450 reductase - 1E reduces Fe3+ in the cytochrome P450-drug complex to Fe2+. the Fe2+-CYP450-drug complex binds O2
  3. 2E from NADPH-CYP450 reducase reduces O2 and forms an “activated oxygen”- Fe2+-CYP450-substrate complex
  4. complex transfers “activated” oxygen to the drug substrate to form the oxidized product, the second activated O atom is used to form H2O
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11
Q

chemically diverse small molecules are converted to:

A

more polar compounds = more water soluble aka hydrophilic

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12
Q

what are 3 functions of CYP450

A
  1. activation/inactivation of drugs
  2. chemical carcinogenesis
  3. participation in physiological pathways
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13
Q

most of the drug metabolizing enzymes are in ____ families

A

CYP 1,2, & 3

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14
Q

in humans, ____ and ____ are the most likely to be responsible for drug biotransformation; their presence in the GI tract is responsible for poor bioavailability of many drugs administered orally

A

CYP3A4/5; CYP2D6

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15
Q

glucuronidation is done by

A

UDP-glucuronosyltransferase

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16
Q

acetylation is done by

A

acetyltransferase

17
Q

in glucuronidation, lipophilic substrate binds to the ____ active site via Phe90

A

UDP-glucuronosyltransderase (enzyme)

18
Q

the “activated” substrate performs nucleophilic attack on C1 of ____

A

UDP-glucuronic acid (cofactor)

19
Q

what enzyme is found in many tissues, including liver

acetylation

A

N-acetyl transderase (NAT)

20
Q

N-acetyl transderase (NAT) requires the cofactor ____ to supple the acetyl group

A

acetyl Co-enzyme A

21
Q

CYP2C9 and 2C19 are involved in what (NSAIDS)

A

the hydroxylation at different positions

22
Q

what carboxylated NSAIDS

A

cytosolic ALDH1 and ALDH2

23
Q

what is pharmacogenomics

A

the study of genes that influence ADME of drugs

24
Q

what are the phase I CYP450 differences

A
  • greyhounds have lower CYP2B11 activoty - results in lower Vd for lipophilic drugs b/c limited fat
  • cats dont have CYP2B6 - hepatic necrosis after receiving diazepam
  • horses have low CYP2D - monesin toxicity
  • mini/micro pigs have increased CYP in general and need higher doses
25
Q

CYP2D6 polymorphism affects drug metabolism

A

poor, intermediate, efficient, or ultrarapid

26
Q

what are the phase II differences

A
  • cats: lack glucoronidation - slow aspirin clearance + acetominophen toxicity
  • Dogs: N-acetyltransferase deficiency & thiopurine methyltransferase
  • pigs: lack sulfate conjugation
  • avian and reptiles: unique AA conjugation
27
Q

phase I metabolism in neonates

A
  • reduced
  • increases progressively during first 6 mo
  • exceeds adult rates by first few years for some drugs
  • slows during adolescence
  • adult rates may be achieved by some drugs 2-4 wks postnatally
28
Q

phase II metabolism neonates

A
  • varies considerably
  • decreased conjugation for bilirubin and acetaminophen
  • normal morphine conjugation
29
Q

effect of age - elderly

A
  • decreases with age
  • phase I - prolonged
  • phase II - no change
    first pass metabolism: reduced 1% per year
30
Q

effect of pregnancy - hepatic clearance

A

affected by progesterone

31
Q

effect of pregnancy - cholestatic effects of estrogen

A

decreases bile secretion

32
Q

effect of diet

A
  • grapefruit juice
  • st john’s wort, other herbal products
33
Q

what are the 3 major categories of CYP inducers

A
  1. phenobarbital
  2. polycylic aromatic hydrocarbons
  3. glucocorticoids
34
Q

what is an inhibitor od CYP450s

A

azole family antifungals

elimination and detox wk 1 (5 decks)

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