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PHAR226 > Enzymes and Transporters > Flashcards

Enzymes and Transporters Flashcards

1
Q

What is the equation for Cls?

A

Cls=Clh+Clr

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2
Q

What are the hepatic clearance mechanisms?

A

phase 1 (P450)
phase 2 (conjugating enzymes)
phase 3 (biliary excretion)

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3
Q

What are the renal clearance mechanisms?

A

glomerular filtration
tubular secretion and reabsorption

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4
Q

What is metabolism?

A

refers to chemical modification of a drug
results in formation of a metabolite
-typically results in inactivation of drug

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5
Q

What is the primary site of metabolism?

A

the liver
metabolism in other organs/tissues may be important for site specific toxicity or drug activity

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6
Q

How does formation of a metabolite help in excretion?

A

the metabolite is more polar so facilitates excretion by the kidney

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7
Q

Differentiate between activation and bioactivation.

A

activation:
-process when a drug is metabolized to a metabolite that has greater pharmacological activity than the administered drug
bioactivation:
-usually reserved to the metabolic activation of a drug to a toxic metabolite

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8
Q

What is phase 1 metabolism?

A

phase 1 pathways primarily involve CYP P450 enzymes
-uncover or introduce a functional group on the drug molecule

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9
Q

Aside from CYP P450, what are some other phase 1 enzymes?

A

xanthine oxidase
alcohol and aldehyde dehydrogenase
epoxidases
esterases

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10
Q

What is the action of CYP P450 enzymes?

A

superfamily of heme containing enzymes responsible for the hydroxylation, oxidation, or reduction of structurally diverse drugs
often referred to as mixed-function oxidases

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11
Q

What is the reason why CYP enzymes metabolize lipophilic drugs?

A

they are typically associated with the smooth ER and active site of the enzyme lies within the ER membrane

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12
Q

Why can CYP P450 enzymes saturate? What is the significance of this?

A

they demonstrate high affinity but low capacity
means many potential drug interactions occur at P450 enzymes

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13
Q

What is the most important CYP enzyme in drug metabolism?

A

CYP 3A4

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14
Q

What is phase 2 metabolism?

A

mediates the conjugation of an endogenous molecule to a functional group on a drug molecule or metabolite
-many of these endogenous molecules are derived from compounds involved in CHO, fat, and protein metabolism

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15
Q

What are the important phase 2 enzymes?

A

UGT
ST
GST
NAT
methyltransferases
amino acid conjugates

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16
Q

What is the action of UGT enzyme?

A

mediate the conjugation of UDPA to drug substrates
-family of enzymes found in smooth ER
-two families: UGT1A and UGT2B
-broad and overlapping drug substrate specificities (many drugs are metabolised by UGT enzymes); includes endogenous cpds

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17
Q

Are UGT enzymes easily saturated?

A

UGT enzymes demonstrate high capacity and therefore are difficult to saturate
-this means few drug interactions occur at UGT enzymes

18
Q

What is the action of sulfotransferase (ST) enzymes?

A

catalyze the conjugation of inorganic sulfate to drugs containing hydroxyl functional groups
-found in the cell cytosol
-the different ST enzymes exhibit overlapping substrate specificities that overlap as well with the UGT enzymes

19
Q

Are ST enzymes easily saturated?

A

ST enzymes show lower capacity and may saturate at higher drug concentrations

20
Q

What is the action of GST enzymes?

A

catalyze the conjugation of glutathione to electrophilic or reactive substrates
-protective function in the cell by mediating the conjugation of glutathione to reactive intermediates and alkylating agents that arise during normal cell metabolism

21
Q

What is the action of NAT enzymes?

A

mediates the conjugation of the acetyl moiety of acetyl-CoA to NAT substrates
-two families: NAT1 and NAT2
-NAT2 demonstrates a genetic polymorphism, which contributes to wide interindividual variability associated with NAT substrates

22
Q

What percentage of drugs on the market are metabolized by CYP3A4? What about CYP2Cs, CYP2D6, and CYP1A2?

A

CYP3A4: ~50% of drugs on the market
CYP2Cs: ~30% of drugs on the market
CYP2D6 and CYP1A2: significant fraction

23
Q

What are the three important reasons to have knowledge of the drug metabolizing enzymes that mediate the elimination of a drug?

A

drug-drug interactions
interpatient variability in drug PK (genetic polymorphism)
effect of disease (major source of variability in response)

24
Q

When do drug-drug interactions occur?

A

when either the PK or PD of one drug is altered by a second drug

25
Q

What do drug-drug interactions impact?

A

absorption, distribution, and/or elimination
may lead to therapeutic ineffectiveness or toxicity

26
Q

True or false: most drug interactions have limited clinical significance

A

true

27
Q

What does the degree of a drug interaction depend on?

A

dose (concentration) or each of the interacting drugs and their time of administration relative to each other

28
Q

Differentiate between competitive inhibition and induction.

A

competitive inhibition:
-acute decrease in metabolism/transport of drug by a simultaneously present drug
=reduction in the elimination of a drug and its accumulation in the body to potentially toxic concentrations
inhibition:
-net increase in enzyme/transporter activity upon exposure to drug due to an increased amount of functional protein
=increased metabolism/transport of a drug such that drug concentrations may drop below the TW and the drug is no longer effective

29
Q

What is the etiology of interpatient variability in drug PK?

A

genetic
physiological/pathophysiological
environmental

30
Q

What are genetic polymorphisms?

A

minor (single nucleotide polymorphism) or major (gene deletion or duplication) change in the nucleotide sequence of a gene encoding a drug metabolizing enzyme/transporter

31
Q

What are the consequences of genetic polymorphisms on PK/PD?

A

reduction in Cls, which will lead to increased t1/2 and potential for drug accumulation
altered metabolite profiles and the production of active or toxic metabolites
altered drug-drug interactions
potential reduction in 1st pass metabolism which increases F
alteration in therapeutic effects of a drug

32
Q

What are the four phases of drug metabolism?

A

phase 0:
-expression of transporters on basolateral membrane to move free drug into hepatocytes
phase 1:
-unbound drug diffuses in and meets CYP enzymes in ER membrane
-hydroxylation, oxidation, reduction
phase 2:
-conjugating enzymes
-polar molecule added for excretion
-polar molecule leaves via transporter
phase 3:
-parent cpd or phase 2 metabolite enters bile via efflux transporters

33
Q

What are transporters?

A

proteins that move solutes (like drugs) across membranes (plasma membrane, organelle membrane)
widely expressed in all cell types
play a role in ADME for many drugs

34
Q

Which phases of metabolism involve transporters?

A

phase 0 and 3

35
Q

Describe solute carrier (SLC) transporters.

A

> 50 families
facilitated diffusion or secondary active
mediate bidirectional movement of drugs; uptake transporters
substrates usually charged or uncharged weakly acidic or basic drugs, inorganic ions, ammonia, other endogenous cps
ex: OCTs, OATs, OATPs, PEPTs

36
Q

Describe ATP binding cassette (ABC) transporters.

A

> 25 families
primary active
efflux; moves drug against a conc gradient
substrates usually lipophilic drugs, endogenous cpds, other polar or charged cpds
ex: MDR1, MRPs, BCRP

36
Q

What is the general importance of transporters?

A

influence drug absorption, distribution, and elimination and therefore overall exposure of the body to the drug
exert a protective function at blood-organ barriers
are determinants of drug levels in tissues/cells
are a site of potential drug-drug interactions or drug-endogenous cpd interactions
saturable which influence F, extent of distribution, and elimination characteristics of a drug
have a host of endogenous functions

37
Q

How much bile does the liver secrete per day?

A

0.25-1L
-stored in gallbladder; secreted into duodenum

38
Q

What kind of molecules are secreted into bile?

A

anions, cations, nonionized molecules
-some drugs; metabolites-glucuronide conjugates

39
Q

What is enterohepatic recirculation?

A

conjugated compound is deconjugated to parent drug and reabsorbed back into systemic circulation
-may lead to a double peak phenomenon when meal consumed after drug administration

40
Q

What is enterohepatic recycling a component of?

A

distribution
-functions to prolong the residence of drugs in the body

PHAR226 (12 decks)

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