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Pharm > 1: Drug Metabolism > Flashcards

1: Drug Metabolism Flashcards

1
Q

2 general outcomes of xenobiotic metabolism

A
  1. termination: loss of therapeutic or toxic activity

2. bioactivation: gain in therapeutic or toxic activity

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2
Q

sites of metabolism throughout the body

A
  • **LIVER
  • GI tract
  • lungs
  • kidneys
  • brain
  • skin
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3
Q

what does first pass metabolism refer to?

A

the liver is the first organ perfused by compounds absorbed in the gut (oral compounds) -> go through here before entering the circulation (affects dose needed)

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4
Q

definition of oral bioavailability

A

fraction of total dose that reaches systemic circulation

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5
Q

4 factors affecting bioavailability

A
  • solubility
  • membrane permeability
  • P-glycoprotein efflux
  • pre-systemic first pass metabolism (intestinal, hepatic)
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6
Q

two phases of drug metabolism

A

I: chemical modification/biotransformation to introduce new functional group or expose group for phase II rxns

II: conjugation of polar group with drug (often kills activity)

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7
Q

what is the importance of drug metabolism?

A

frequently the most important determinant of duration and intensity of drug response

  • alters pharmacological activities of drugs
  • influences half-life
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8
Q

3 ways to terminate xenobiotic action

A
  • bioinactivation
  • detoxification
  • elimination
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9
Q

2 ways in which metabolism causes bioactivation

A
  • prodrugs

- toxification (particularly via phase I rxns)

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10
Q

bioinactivation vs. detoxification

A

terminology has more to do with intent:

  • bioinactivation -> stop action of therapeutic drugs
  • detoxification -> elimination of toxicity of a toxin
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11
Q

how does metabolism change drugs to aid in elimination?

A

increase polarity of the drugs:

  • decrease lipid solubility
  • increase water solubility

NEED BOTH

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12
Q

definition of prodrug

A

drug metabolite(s) may be more active than the parent compound, or the parent may require activation for the biological activity (bioactivation)

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13
Q

example of toxification

A

polyaromatic hydrocarbons from cigarette smoke: phase I enzymes metabolize them into planar epoxide compounds, which can intercalate into DNA (mutagenic) –> thought to be the basis of carcinogenicity of cigarette smoke

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14
Q

why are most adverse reactions related to drug metabolism idiosyncratic (unpredictable)?

A

b/c there are many poorly understood factors:

  • which proteins react with reactive metabolite?
  • which protein modifications lead to toxicity and how?
  • many risk factors influence reactive metabolite formation and inactivation
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15
Q

most frequent reason that new therapeutic agents are not approved by FDA?

A

drug-induced hepatic damage

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16
Q

reactions that occur in phase I metabolism

A

typically oxidation

-also reduction, hydrolysis

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17
Q

typical enzyme of phase I reactions? what other substrates are necessary?

A 
cytochrome P450 (CYP) 
-utilizes NADPH and O2
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18
Q

what happens to the metabolites of phase I reactions? 2 possible outcomes

A
  1. excreted if sufficiently polar

2. functionalized to undergo subsequent phase II rxn

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19
Q

what determines what the substrates will be for the CYP enzymes?

A

the shape of the protein determines the size/shape of entry and exit access pathways, which therefore determines which substrates will fit and which will not

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20
Q

in the cytochrome P450 system, what enzyme plays the electron transport role? where do the electrons come from?

A

P450 reductase, utilizing an electron from NADPH

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21
Q

what are the three most important/prevalent CYPs involved in human drug metabolism?

A
  • CYP3A4/5
  • CYP2D6
  • CYP2C8/9
22
Q

why is it therapeutically important that the CYPs are responsible for so much of drug metabolism?

A

significant chance for drug-drug interactions during multi-drug treatment –> when metabolized by the same CYP isoform, only one of the two drugs can be metabolized by the same CYP entity at the same time –> increased half-life, which may cause toxicity

23
Q

describe the catalytic center of the CYPs

A
  • contains an iron-heme cofactor
  • iron coordinated to 4 N’s of the heme, to 1 thiolate ligand from Cys, and to 1 water molecule (in native state)
  • upon reduction, maximal light absorption “soret peak” at 450 nm
24
Q

describe the reaction mechanism involving the catalytic iron-heme cofactor of the CYP catalytic site

A

ferric, low spin –> ferric, high spin –> ferrous –> ferric, hydroperoxide –> oxyferryl, compound I –> ferric –> repeat from start

25
Q

describe 6 reactions catalyzed by CYPs

A
  1. aromatic hydroxylation
  2. N-oxidation (add =O onto amine group)
  3. N-dealkylation (-CH3 -> -H on an amine)
  4. O-dealkylation
  5. Sulfoxidation (add =O to the S of an R-S-R’)
  6. Deamination (add -OH to a C that is also attached to an amine -> unstable -> rearranges into a ketone + releases amine)
26
Q

what are some intrinsic factors that are important in determining which CYPs can catalyze which metabolic reactions?

A
  • topography of protein binding site
  • steric hindrance of the access to the catalytic heme group
  • how the ligand binds
  • ligand binding affinity
  • intrinsic reactivity of chemical group that is in close proximity to the catalytic center
  • accessibility of chemical group
27
Q

what are three factors that determine binding strength?

A
  • coordination strength with heme iron
  • hydrophobic contacts with binding site of CYP
  • specific contacts (H-bonds) with binding site residues
28
Q

name two ways in which inhibitors may outcompete for binding sites on CYPs

A
  • molecules with N as 6th iron-coordinating ligand have stronger affinity to the heme iron than molecules that coordinate with O or C atoms
  • additional hydrophobic contacts stabilize the ligand-protein binding
29
Q

does the substrate always have to do the inhibition? explain

A

no - sometimes the metabolite is the inhibitor rather than the substrate itself

30
Q

does inhibition inhibit metabolism of all substrates of a specific CYP? give example

A

not necessarily - different binding site moieties
(inhibitor might block one substrate from binding, but not block another which accesses catalytic site from another entry point/route)

ex: cimetidine inhibits warfarin metabolism of CYP2C, but does not inhibit ibuprofen metabolism

31
Q

definition of mechanism-based inhibition (MBI)

A

aka suicide inhibition
-metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues in the binding site -> further metabolism of same or other drug is delayed as CYP needs to be resynthesized

32
Q

definition of induction

A

administration of one drug causes increase in the rate of an enzyme/induces transcription of more CYP genes -> means you could lower efficacy of that drug or another drug metabolized by the induced enzyme b/c it will now be metabolized faster

ex: rifampin is an inducer of alfentanil (opiod analgesic drug)

33
Q

what is the significance of induction?

A
  • reduced plasma concentrations of drug

- increased toxicity if reactive metabolites are formed

34
Q

describe the molecular basis of induction

A

drug or substance binds with nuclear receptor -> receptor dimerizes -> enters nucleus -> induces transcription of new CYPs

35
Q

examples of induction by bile acids, xenobiotics, and fatty acids

A

bile acids –> VDR, PXR—(each induces all of the following)–> CYP2A, CYP2B, CYP2C, CYP3A
bile acids –> FXR –> CYP3A, CYP7A1

xenobiotics –> CAR, PXR –(each induces all of the following)–> CYP2A, CYP2B, CYP2C, CYP3A

fatty acids –> PPARa –> CYP4A, CYP7A1

36
Q

example of how induction can lead to genotoxicity/carcinogenicity

A

CYP1A1 metabolizes PAH, so if CYP1A1 is induced –> increase reactive planar epoxide production -> increase intercalation of epoxides into DNA -> increased formation of adducts –> toxicity

37
Q

definition of drug-drug interactions (DDI)

A

when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food, or chemical

38
Q

what percent of all drug-drug interactions involve CYPs?

A

about 50%

39
Q

what is the significance of drug-drug interactions?

A

adverse drug reactions, in particular for:

  • drugs with high first-pass metabolism (low bioavailability)
  • narrow therapeutic indices
  • steep dose-response relationships
  • multidrug therapies
40
Q

what is an example of how drug-drug interactions can be beneficial?

A

lopinavir and ritonavir (HIV protease inhibitors)

lopinavir: substrate of CYP3A4, low bioavailability
ritonavir: inhibitor of CYP3A4, higher bioavailability

combination therapy (Kaletra) gives you higher oral bioavailability of lopinavir so that it is more effective

41
Q

name the most well-known food-drug interaction

A

grapefruit inhibits CYP3A4 b/c it contains:

  • bergamottin (MBI)
  • 6’,7’-dihydroxybergamottin (MBI)
  • naringin (inhibitor of CYP3A4)
42
Q

name 6 other phase I enzymes

A
  • flavin-containing mono-oxygenase
  • alcohol DH
  • MAO
  • esterase
  • amidase
  • epoxide hydrolase
43
Q

describe phase II drug metabolism

A

these rxns couple drug or activated drug (by phase I rxns) with conjugates (typically polar groups) –> conjugate is more water soluble and less lipid soluble –> significant increase in urinary excretion

typically bioinactivates and detoxifies (but exceptions)

44
Q

list two exceptions to the idea that phase II metabolism typically bioinactivates and detoxifies compounds

A
  1. bioactivation: morphine –> 6-glucuronide

2. toxification: carcinogenicity, allergic rxns

45
Q

name the most dominant phase II enzyme

A

UGTs = uridine 5’-diphosphate [UDP]-glucuronosyl transferases

46
Q

why are UGT’s the most dominant phase II enzyme?

A
  • readily available supply of glucose and UTP in liver -> will react in 4 enzymatic rxns (using ATP, NAD) to uridine diphosphate glucuronic acid (UDPGA)
  • many fxnal groups can form glucuronide conjugates
    • O-glucuronidation (-COOH, -OH)
    • N-glucuronidation (-NH2)
    • S-glucuronidation (-SH)
47
Q

how can phase I metabolites be further metabolized by UGI without a long path between both reactions?

A

have UGT and P450 spatially co-localized on the ER

48
Q

name 4 other phase II enzymes besides UGT

A
  • SULT = sulfotransferases
  • GST = glutathione S-transferase
  • N-acetyltransferases
  • O-, N-, S-methylation by methyltransferases
49
Q

does age affect drug metabolism? (here, with babies)

A

yes, it can:

  • CYP3A4/7 expression is different pre-natal and post-natal (ex)
  • babies have immature UGT systems
  • most xenobiotics in maternal circulation cross placenta + only placental efflux pump is P-gp
  • can get accumulation of drugs or reactive metabolites –> induction of CYP1A1 –> toxic/carcinogenic metabolites
50
Q

describe how drug metabolism is changed in the elderly (4 ways)

A
  • drug-drug interactions when taking multiple drugs
  • decreased hepatic blood flow –> reduced 1st pass metabolism
  • decreased hepatic mass –> slight reduction of some phase I metabolic rxns
  • decreased renal blood flow –> decreased renal excretion
51
Q

can disease affect drug metabolism? examples

A

yes:
- acute and chronic liver diseases can alter hepatic metabolism
- cardiac disease can decrease blood flow to liver -> reduced hepatic clearance

52
Q

do genetic factors affect drug metabolism?

A

yes:
- poor metabolizers (PM)
- greater potential for drug-drug interactions and AE
- slower bioactivation of prodrug (lower efficacy)
- extensive metabolizers (EM) –> normal
- ultrarapid metabolizers (URM)
- greater rate of drug elimination (lower efficacy)
- greater potential for generating toxic metabolites

Pharm (19 decks)

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