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Pharmacology > 03&04 - Biotransformation > Flashcards

03&04 - Biotransformation Flashcards

1
Q

phase 1 reaction result in

A

-relatively minor chemical modification of the parent compound

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2
Q

phase 1 reactions may result in the formation of functional groups which serve

A

as site for conjugation rxns

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3
Q

phase 1 reaction metabolite formed is more —

A

polar (more water soluble; less lipid soluble)

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4
Q

what are phase II reactions

A

these reactions are conjugations (i.e.. synthetic rxn with additional of another molecule)

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5
Q

phase II reaction drug or metabolite is rendered more — and —

A
  • more polar

- less lipid soluble

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6
Q

phase II rxs with rare exception (eg. morphine), metabolites formed are

A

pharmacologically inactive

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7
Q

typical phase 1 reactions uses what 3 types of runs

A
  1. oxiations
  2. hydrolysis
  3. reductions
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8
Q

example of oxidations of typical phase 1 rxns

A
  • cytochrome P450-linked (mainly in liver)
  • epoxide hydrolase
  • alcohol, aldehyde dehydrogenase
  • xanthine oxidase (purines)
  • monoamine oxidase (amines; mitochondria)
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9
Q

example of hydrolysis

A

ester and amide

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10
Q

examples of reductions

A

azo and nitro

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11
Q

what is cytochrome P-450

A
  • mediates oxidation rxns (mixed-function oxidase)
  • ancient “superfamily” with extensive phlyogenetic distribution
  • 18 gene families in humans, encoding > 50 enzymes
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12
Q

CYP is an abbreviation for

A

cytochrome P450

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13
Q

CYP3 designates

A

family (>40% sequence homology)

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14
Q

CYP A designates

A

sub-family (>55% sequence homology)

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15
Q

CYP4 designates

A

specific gene/enzyme

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16
Q

CYP rxns are characterized as

A
  • a mixed-function-oxidase, dependent on NADPH and molecular O2
  • sort electron transport chain located in SER of liver and other organs
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17
Q

various isoforms of cytochrome P450 catalyze what

A

the oxidation rxn with a low degree of substrate specificity

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18
Q

substrates of CYP rxns must be

A

lipid soluble

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19
Q

what factors influence drug metabolism

A
  • genetic P450 pattern/variant
  • exposure to inducers
  • up-regulation
  • inhibition of P450 isoforms
  • hepatic disease
  • age
  • sex
  • nutritional status/diet
  • adrenal and thyroid function
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20
Q

genetic p450 pattern/variant alleles yields an average of

A

6 to 30 fold variation in the average rate of drug metabolism
-individual differences for certain isoforms subject to pharmacogenetic variation can be even more striking

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21
Q

how can exposure to inducers (drug/ environment) influence drug metabolism

A

-content of many CYPs can be increased by exposure to certain drugs and exogenous compounds (2x-3x)

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22
Q

up-regulation usually occurs by

A

enhanced gene transcription following prolonged exposure to inducer

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23
Q

consequences of influencing drug metabolism

A
  • increased rate of metabolism
  • enhanced first-pass effect
  • reduced bioavailability
  • decreased [plasma]
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24
Q

inhibition of P450 isoforms may be due to

A

competition for enzyme active site, inactivation, or interactions with the heme group

25
Q

consequences of inhibiting P450 isoforms

A
  • increase [plasma] of the parent drug
  • reduction in metabolite
  • exaggerated and prolonged pharmacological effects
  • increased likelihood of drug toxicity
26
Q

what CYP enzymes are responsible for metabolizing most clinically important drugs

A

CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4,5

27
Q

what CYP enzymes are primarily involved in drug metabolism

A

CYP1,2,3

28
Q

drug metabolism represents

A

a potential source of significant drug interactions
-there are large individual differences in the average rate of drug metabolism due to genetic and environmental influences

29
Q

what are 3 biliary-fecal routes

A
  1. transport systems
  2. biliary secretion
  3. enterohepatic cycle
30
Q

where are biliary fecal-route transport systems located

A

in the heptocyte

31
Q

function of biliary fecal route transport systems

A

actively uptake and secrete drugs and metabolites into the bile

32
Q

what are biliary secretions

A

amphipathic, lipid-soluble conjugated metabolites with a MW of >300 may be secreted (MPR2) by the liver into the bile

33
Q

enterohepatic cycle

A

active drug of its metabolite can be excreted in the feces or reabsorbed

34
Q

glucuronide conjugates can be secreted and recovered to

A

the free,a chive drug in the intestinal lumen by bacterial enzymes

35
Q

what is the formula for hepatic clearance

A

Cl organ= Q [CA-CV] = Q x E

Q= flow
CA= [arterial]
CV = [venous]
36
Q

(CA-CV/CA) can be referred to as

A

the extraction ration of the drug (E)

37
Q

what is intrinsic clearance

A

the intrinsic ability of the liver to eliminate a drug in the absence limitations imposed by blood flow

38
Q

intrinsic clearance is a measure of

A

the Michaelis-Menten kinetic parameters for the eliminating process (ie. Vmax/Km)

39
Q

high intrinsic clearance is relative to

A

blood flow

40
Q

high intrinsic clearance is approximated and determined by

A

hepatic blood flow

41
Q

how will decrease in blood flow affect high intrinsic clearance

A

will decrease Cl

decrease in blood flow due to aging, disease

42
Q

will changes in plasma protein binding or enzyme activity affect high intrinsic clearance

A

will have minimal effect

43
Q

low intrinsic clearance is relative to what

A

blood flow

44
Q

low intrinsic clearance will be proportion to what

A

the unbound fraction of the drug in blood and the intrinsic clearance (ie. enzyme activity/biliary ecretion)

45
Q

will changes in blood flow affect low intrinsic clearance

A

not significant effect on clearance

46
Q

what will impact low intrinsic clearance

A

enzyme induction or changes in protein binding

47
Q

what is the first-pass effect

A

orally administered drugs must pass through the liver before gaining access to the systemic circulation

48
Q

what drugs will demonstrate reduced or low bioavailability

A
  • drugs with high hepatic extractions

- drugs which are metabolized rapidly compared with their rate of absorption

49
Q

what are the renal excretion methods

A
  1. glomerular filtration
  2. tubular secretion (active transport)
  3. tubular reabsorption
50
Q

glomerular filtration clears

A

unbound drug

51
Q

tubular secretion (active transport) occurs where

A

proximal tubule; energy dependent

52
Q

when does tubular secretion (active transport occur)

A

as rate approaches renal blood flow?

53
Q

tubular secretion (active transport) are unaffected by what

A

protein binding

54
Q

tubular reabsorption

A
  • concentration gradient
  • Kp
  • pKa
  • influence of urinary pH
55
Q

Renal clearance formula (ml/min)

A

(UxV)/P

U= concentration of drug in urine
V=volume of urine excreted per minute
P= concentration of drug in plasma

56
Q

clearance value of a drug filtered and completely reabsorbed

A

Cl=0

57
Q

clearance of a drug filtered and not reabsorbed

A

Cl~120ml/min

58
Q

clearance of a drug filtered and (max) secreted

A

Cl~650ml/min

Pharmacology (23 decks)

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