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ADME - Pharma > ADME > Flashcards

ADME Flashcards

1
Q

Lipinski’s rule (rule of 5)

A
  • H bond donor <5
  • H-bond acceptor <10
  • MW < 500
  • cLogP <5
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2
Q

Explain Lipophilicity

A

Tendency of a compound to partition into a non-polar lipid matrix versus an aqueous
Traditionally, octanol and water are used

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3
Q

Explain logP

A

Log10 of the partition coefficient if the compound in organic/water layers, where all the molecules are neutral

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4
Q

Explain LogD

A

Log10 of the distribution coefficient if the compound in organic/water layers at a specified pH. Molecules might be ions or neutral

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5
Q

Explain pKa

A

Compound’s ionizability in an aqueous solution

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6
Q

Solubility is determined by:

A
  • Compound structure
  • State (solid/liquid)
  • Solvent (type, pH, temperature)
  • Measurement methods
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7
Q

Solubility is affected by:

A

Physicochemical properties:

  • lipophilicity
  • size
  • pKa
  • crystal lattice energy (crystal stacking, meeting point)
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8
Q

What are the modification strategies to improve solubility?

7

A
  • Addition is ionizable groups
  • Reduction of LogP
  • Addition of H-bonds
  • Addition of polar groups
  • Reduction of MW
  • Out-of-plane substitution
  • Construction of a prodrug
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9
Q

What are the modification strategies for improving dissolution rate?
(4)

A
  • Reduce the particle size
  • Prepare am oral solution
  • Formulation with surfactants
  • Prepare a salt form
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10
Q

How much of potential drugs are excluded by the blood-brain barrier when going through the brain?

A

As much as 98%

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11
Q

What is the efflux?

A

It is the transport of a molecule out of a cell (for example with p-glycoprotein, Pgp)

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12
Q

Structure modifications strategies to improve brain penetration:
(6)

A
  • Reduce Pgp efflux
  • Reduce number of H-bond
  • Increase lipophilicity
  • Reduce MW
  • Replace carboxylic groups
  • Add intramolecular H-bonds
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13
Q

What are the two phases on metabolism and what is their mechanism?

A

Phase 1: modifications of the molecular structure

Phase 2: addition of polar groups to the molecular structure

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14
Q

Which ADME parameters does metabolism affect?

A

It increases clearance, reduces exposure, and is a major cause of low bioavailability

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15
Q

What is presystemic/first pass clearance?

A

It is when a drug is metabolised prior to reaching systemic circulation. It can occur in the gut and liver

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16
Q

What kind of interaction can occur when two molecules are co-injected?

A

One drug can inhibit the metabolism of the other. This could lead to toxic effects

17
Q

What are the common phase 1 metabolic reactions?

A

Aliphatic oxidation, aromatic oxidation, alcohol oxidation, dehydrogenation, epoxidation, (N,S,O)-dealkylation
Réductions can also occur

18
Q

What moiety can be added during phase 2 metabolism?

A

Glucuronic acid

The mechanism is called glucuronidation

19
Q

Other than glucuronidation, what other polar moieties can be added during phase 2 metabolism?

A

Sulfations, acetylation, glycination and methylation can also occur

20
Q

What is the main effect of metabolic stability?

A

It affects pharmacokinetics (PK)

21
Q

The half-life determines the dose regimen on how…

A

How often the drug must be administered

22
Q

The oral bioavailability determines the dose regimen on how….

A

How much of the drug should be administered

23
Q

Inhibition of the P450 cytochrome family are part of phase … metabolism

A

Phase 1 metabolism

24
Q

What are the structure modification strategies for phase 1 metabolism?
(8)

A
  • Block the metabolite site by adding Fluorine
  • Block the metabolite site by adding other blocking groups
  • Remove labile functional groups
  • Cyclization
  • Change ring size
  • Change chirality
  • Reduce lipophilicity
  • Replace unstable groups
25
Q

What king of blocking groups can be added to block phase 1 metabolism?

A

Chlorine, but also more bulky aliphatic groups

26
Q

What are the structure modification strategies for phase 2 metabolism?
(3)

A
  • Introduce electron-withdrawing groups and steric hindrance
  • Change phenolic hydroxyl to cyclic urea or thiourea
  • Change phenolic hydroxyl to prodrug
27
Q

What is a bioisostere?

A

It is a chemical substituent with similar physical/chemical properties. It produces similar biological properties

28
Q

Plasma stability is important because…

A

Hydrolysis in plasma can be a major cause of compound clearance

29
Q

Which functional groups are susceptible to plasma degradation?
(6)

A

Esters, amides, carbamates, lactams, lactones, sulfonamides

30
Q

What kind of approach can take advantage of plasma reactions?

A

A prodrug approach; typically, esters are prepared, and activated through hydrolysis

31
Q

What are antedrugs?

A

Antedrugs are active locally but rapidly degrade to inactive compounds once they reach the bloodstream.

32
Q

What is the purpose of antedrugs?

A

It is to reduce side effects by minimising systemic toxicity of the drug

33
Q

What are the structure modification strategies to improve plasma stability?
(3)

A
  • Substitute an amide for an ester
  • Increase steric hindrance
  • Electron withdrawing groups decrease plasma stability (for antedrugs)
34
Q

During the drug discovery process, drugs are exposed to many solutions:

A
  • Organic solvents
  • Aqueous buffers
  • Bioassay buffers
  • Dosing solutions
  • GI tract
35
Q

What is an excipient?

A

It is a secondary substance in a medication that can help stabilise/confer a therapeutic of the drug. It doesn’t react with the active drug

36
Q

What are the structure modification strategies to improve solution stability?
(4)

A
  • Eliminate/modify unstable groups
  • Add an electron withdrawing group
  • Isosteric replacement of labile functional group
  • Increase steric hindrance
37
Q

What are the applications of solution stability data?

7

A
  • Provide an early alert to liabilities
  • Selection of conditions for compound purification
  • Develop structure-stability relationship
  • Diagnose poor in vivo bioassay performance
  • Diagnose poor in vivo performance
  • Prioritize compound for in vivo animal studies
  • Structure elucidation of solution stability products (using LC-MS) guides synthetic optimization
38
Q

What can reduce in vivo exposure in the stomach/intestine?

A

Low pH and enzymatic hydrolysis

39
Q

How does a software calculate the LogP of a new molecule?

A

By breaking up the structure in substructures where the value is known, and then adding all these values

ADME - Pharma (1 decks)

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