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PHAR221 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Drug metabolism

A

is the chemical transformation of a drug into one or more products within the body

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2
Q

Drug metabolism does

A
  • not occur for all drugs (like lithium)
  • protect the body against xenobiotics (e.g., drugs, toxins) - liver (primary) and other organs/tissues
  • first-pass (pre-systemic) metabolism (gut wall & liver)- ↓ bioavailability of orally administered drugs
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3
Q

Drug metabolism is mediated by what and involves what reactions

A

enzymes

oxidation, reduction,
hydrolysis and/or conjugation

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4
Q

drug metabolising enzymes (DMEs)

A
  • Rich in liver
  • On membrane of ER of hepatocytes (liver cell like CYP450)
  • In cytosol (AD) or mitochondria (AldD) and other tissues/organs like the brain, lungs, plasma and intestines
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5
Q

First pass

A

the substance degradation of an orally administered drug caused by enzyme metabolism in the liver before the drug reaches the systemic circulation. It decrease the bioavailability administered of drugs

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6
Q

Phase 1 Metabolism

A

Oxidation, reduction, hydrolysis
Parent drug (P1) metabolites (P2) conjugated metabolites

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7
Q

conjugated metabolites

A

virtually always inactive, very polar and/or ionized, and easily excreted.

(products of Phase II reactions)

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8
Q

Phase 1 metabolism ethanol example

A

Ethanol (CH3CH2OH)

ADH (Alcohol Dehydrogenase) - removes H from parent drug

Forms: Acetaldehyde (CH3CH2O)

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9
Q

Phase 1 metabolism tenofovir disoproxil example hydrolysis

A
  • hydrolysis ester and (less readily) amide bonds
  • prodrug - a useful strategy to ↑ oral drug delivery
    • molecules with little or no pharmacological activity
      that are converted in vivo to active drugs

[Tenofovir Disoproxil

esterase

Tenofovir - not active and needs phosphorylation]

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10
Q
A
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11
Q

Phase 2 metabolic reactions

A
  • Glucuronidation (UGT)
  • Sulfation (SULT)
  • Glutathione conjugation (GST)
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12
Q

Phase 2 metabolism

A

Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its Phase 1 metabolites

attach a polar endogenous molecule to a functional group in a drug - ↑ hydrophilicity to facilitate excretion

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13
Q

Glucuronidation

A

UGT (UDP glucuronosyltransferase) transfers glucuronic acid from UDP-glucuronic acid to a drug or drug metabolite (UDP = uridine diphosphate)

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14
Q

sulfation

A

SULT (Sulfotransferase) transfers sulfonate group from PAPS to a drug or drug metabolite (PAPS, 3’-
phosphoadenosine–5’-phosphosulfate)

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15
Q

glutathione conjugation

A

GST (glutathione-S-transferase) attach glutathione (Glu-Cys-Gly) to a drug or drug metabolite

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16
Q

Morphine P2

A

M -UGT2B7-> morphine-3-glucuronide (Major/pharm-inactive)
or
M -UGT2B7-> morphine-6-glucuronide (Minor/Pharm-active)

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17
Q

NAPQI

A

(the toxic metabolite of paracetamol) - detoxification by glutathione conjugation

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18
Q

Outcomes of drug metabolism

A

(I) increases molecular size and hydrophilicity
(II) decreases drug elimination half-life (t1/2)
(III) alters pharmacological activity or induces toxicity

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19
Q

D.Meta outcomes
Increases molecular size and hydrophilicity

A
  • reduce tendency to accumulate
  • facilitate renal excretion
  • If drug is hydrophilic it doesn’t undergo metabolism in liver and is removed by renal excretion.
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20
Q

Phase 1–> functional groups
Lipophilic

A

Goes through hepatic Metabolism to make hydrophilic metabolites that go through hepatobiliary excretion to either bile or renal excretion.

21
Q

D.Meta outcomes
Decreases drug elimination half-life (t1/2) definition

A

Drug elimination half-life (t1/2) is the time taken for the drug plasma concentration to decrease by 50%
and is calculated during the elimination phase

22
Q

Plasma conc without drug metabolism

A

Has a longer half life

23
Q

Plasma conc with drug metabolism

A

Shorter half life

24
Q

D.Meta outcomes
Alters pharmacological activity or induces toxicity

A
  • Drug metabolism can terminate the action of a drug
  • Drug metabolism generates metabolites that have their own chemical properties and may be
    biologically active or inert
    parent drug
25
Q

e.g., morphine →
pharmacologically in/active

A

morphine-3-glucuronide(in)
morphine-6-glucuronide

26
Q

paracetamol →
toxic and reactive

A

NAPQI

27
Q

codeine →
pharmacologically active

A

morphine

28
Q

DMEs - cytochrome P450 (CYP)

A
  • metabolism of drugs and xenobiotics - CYP1, CYP2 and CYP3
  • 57 CYP genes in human genome
    • classified into 18 families and 43 subfamilies
29
Q

key drug metabolising CYPs

A

CYP3A4
CYP2D6

30
Q

CYPs are ___-containing proteins

A

heme

31
Q

CYPs use _____ (cofactor) and __ to metabolise xenobiotics/drugs (SH)

A

NADPH
O2
- 1 for oxidation
- 1 added to H+ to make H2O

32
Q

CYP-POR (P450 oxidoreductase) complex- electron transfer

A

NADPH
FAD
FMN
P450

33
Q

CYP450 found on ____ ____
of hepatocytes

Liver homogenates undergo sequential______ at ultra-high speed

CYP450 concentrated in_____ (formed
from ER fragments)

Used in __ ____studies to investigate drug
metabolism

A

endoplasmic reticulum (ER)

centrifugation

microsomes

in vitro

34
Q

microsomes

A

Microsomes are small sealed vesicles that originate from fragmented cell membranes (often the endoplasmic reticulum [ER]).

35
Q

Drug interaction definition

A

Process by which a substance alters the action and/or kinetics of a drug

-e.g., different CYPs have distinct but often overlapping substrate specificity

36
Q

Drug metabolism can be modified by endogenous and exogenous factors such as

A

genetics, disease
states and xenobiotics.

37
Q

CYP-mediated drug-drug interactions

A

(i) CYP induction
(ii) CYP inhibition

38
Q

CYP induction

A

drugs cause ↑ CYP expression
-rifampicin (treat tuberculosis)
- some antiepileptic drugs, e.g.,
o phenytoin
o phenobarbital*
o carbamazepine

39
Q

CYP inhibition

A

drugs compete for the active site of an enzyme when co-administered

  • a CYP inhibitor itself may or may not be a substrate for the enzyme
40
Q

Competitive Inhibition

A

substance that resembles the normal substrate competes with the substrate for the active site

41
Q

mechanism-based inhibition

A

irreversible inhibition of an enzyme due to formation of a complex between the enzyme and a reactive
metabolite via covalent bonding, e.g., ritonavir* and cobicistat*

42
Q

Outcomes of CYP inhibition

A

(a) exaggerated drug effects or toxicity due to reduced hepatic metabolism
(b) lack of drug effects due to impaired metabolic activation of prodrug

43
Q

Hepatic Metabolism

A

most drugs, once absorbed, are distributed to sites of action and then undergo metabolic changes when returned in blood through the liver.

44
Q

rifampicin is a CYP3A4_____

A

inducer

45
Q

itraconazole is a CYP3A4___

A

inhibitor

46
Q

Cobicistat

A
  • CYP3A4 inhibitor
  • no antiretroviral activity
47
Q

hepatic metabolism of alcohol

A
  • alcohol dehydrogenase (primary and saturable)
  • CYP2E1
48
Q

Alcohol and Paracetamol

A

Ethanol induces enzyme activity resulting in an increase in the metabolism of paracetamol to NAPQI

PHAR221 (23 decks)

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