03&04 - Biotransformation Flashcards Preview

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Flashcards in 03&04 - Biotransformation Deck (58):
1

phase 1 reaction result in

-relatively minor chemical modification of the parent compound

2

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

as site for conjugation rxns

3

phase 1 reaction metabolite formed is more ---

polar (more water soluble; less lipid soluble)

4

what are phase II reactions

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

5

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

-more polar
-less lipid soluble

6

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

pharmacologically inactive

7

typical phase 1 reactions uses what 3 types of runs

1. oxiations
2. hydrolysis
3. reductions

8

example of oxidations of typical phase 1 rxns

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

9

example of hydrolysis

ester and amide

10

examples of reductions

azo and nitro

11

what is cytochrome P-450

-mediates oxidation rxns (mixed-function oxidase)
-ancient "superfamily" with extensive phlyogenetic distribution
-18 gene families in humans, encoding > 50 enzymes

12

CYP is an abbreviation for

cytochrome P450

13

CYP3 designates

family (>40% sequence homology)

14

CYP A designates

sub-family (>55% sequence homology)

15

CYP4 designates

specific gene/enzyme

16

CYP rxns are characterized as

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

17

various isoforms of cytochrome P450 catalyze what

the oxidation rxn with a low degree of substrate specificity

18

substrates of CYP rxns must be

lipid soluble

19

what factors influence drug metabolism

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

20

genetic p450 pattern/variant alleles yields an average of

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

21

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

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

22

up-regulation usually occurs by

enhanced gene transcription following prolonged exposure to inducer

23

consequences of influencing drug metabolism

-increased rate of metabolism
-enhanced first-pass effect
-reduced bioavailability
-decreased [plasma]

24

inhibition of P450 isoforms may be due to

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

25

consequences of inhibiting P450 isoforms

-increase [plasma] of the parent drug
-reduction in metabolite
-exaggerated and prolonged pharmacological effects
-increased likelihood of drug toxicity

26

what CYP enzymes are responsible for metabolizing most clinically important drugs

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

27

what CYP enzymes are primarily involved in drug metabolism

CYP1,2,3

28

drug metabolism represents

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

what are 3 biliary-fecal routes

1. transport systems
2. biliary secretion
3. enterohepatic cycle

30

where are biliary fecal-route transport systems located

in the heptocyte

31

function of biliary fecal route transport systems

actively uptake and secrete drugs and metabolites into the bile

32

what are biliary secretions

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

33

enterohepatic cycle

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

34

glucuronide conjugates can be secreted and recovered to

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

35

what is the formula for hepatic clearance

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

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

36

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

the extraction ration of the drug (E)

37

what is intrinsic clearance

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

38

intrinsic clearance is a measure of

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

39

high intrinsic clearance is relative to

blood flow

40

high intrinsic clearance is approximated and determined by

hepatic blood flow

41

how will decrease in blood flow affect high intrinsic clearance

will decrease Cl
(decrease in blood flow due to aging, disease)

42

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

will have minimal effect

43

low intrinsic clearance is relative to what

blood flow

44

low intrinsic clearance will be proportion to what

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

45

will changes in blood flow affect low intrinsic clearance

not significant effect on clearance

46

what will impact low intrinsic clearance

enzyme induction or changes in protein binding

47

what is the first-pass effect

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

48

what drugs will demonstrate reduced or low bioavailability

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

49

what are the renal excretion methods

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

50

glomerular filtration clears

unbound drug

51

tubular secretion (active transport) occurs where

proximal tubule; energy dependent

52

when does tubular secretion (active transport occur)

as rate approaches renal blood flow?

53

tubular secretion (active transport) are unaffected by what

protein binding

54

tubular reabsorption

-concentration gradient
-Kp
-pKa
-influence of urinary pH

55

Renal clearance formula (ml/min)

(UxV)/P

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

56

clearance value of a drug filtered and completely reabsorbed

Cl=0

57

clearance of a drug filtered and not reabsorbed

Cl~120ml/min

58

clearance of a drug filtered and (max) secreted

Cl~650ml/min