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Chem390 > Drug Solubility, Metabolism, Resistance - Brent Copp > Flashcards

Drug Solubility, Metabolism, Resistance - Brent Copp Flashcards

0
Q

What are the main areas of the drug development journey which cause the drug to fail?

A

Metabolism and pharmacokinetics

Toxicology

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1
Q

What is the significance of the saying “fail early, fail cheap”

A

Only 20% of compounds entering human testing ultimately get approved for sale,
So if a drug is failed in the earlier stages, it can safe the pharmaceutical company a lot of money

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2
Q

Why does failure occur and what can be done about this?

A

Failure of a drug primarily occurs due to efficacy, toxicity and pharmacokinetics,
We can bring the PK and ADME studies earlier into the drug discovery phase to fail the drug early

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3
Q

Why is the drug discovery pathway a non linear path?

A

We should start on our animal studies really early on instead of synthesising and testing analogues in vivo.
After we do animal studies, we need to check the biological activity.
We also need to check the biological activity following every alteration we make to the drug

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4
Q

What is the action of a drug dependent on?

A

The drug reaching its site of action in a sufficient concentration for a long enough period of time for a significant pharmacological response to occur

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5
Q

What does the journey of a drug reaching its site of action dependent on?

A

Route of administration
Efficiency of drug absorption
Rate at which drug is transported to site of action
Rate of drug metabolism on route and at site of action
Rate of drug excretion
Age, gender, physiological state of patient

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6
Q

What is pharmacokinetics?

A

The study of the relationship between drug response in the patient and these factors

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7
Q

Why are pharmacokinetic tests improtant?

A

Without the knowledge gained from PK studies, patients may suffer:

From toxic drugs accumulating, leading to death
Useful drugs may have no benefit due to doses being too small
Drugs may be metabolised to other products

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8
Q

Why are in vitro assays and pharmacokinetic studies better observed in vivo?

A

There are limitations on the accuracy of computational models

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9
Q

What is absorption?

A

The movement of a drug from its site administration into the blood

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10
Q

What does absorption depend on?

A

Rate of dissolution- faster dissolution, faster abosrption, faster effects

Surface area- larger drug or organ=larger surface area= faster absorption

Blood flow- greater blood flow at the site of admin = faster absorption

Lipid solubility- high lipid solubility = faster absorption

PH partitioning - drug that ionises in the blood and not at the site of admin will absorb more quickly

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11
Q

What does drug absorption rely on?

A

The passage through membranes to reach the blood

Most of which is by passive diffusion

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12
Q

What is the journey of drugs administered orally?

A

They pass through the stomach membrane or intestinal epithelium, then the plasma membrane

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13
Q

What are important parameters related to absorption?

A

PKa,
Solubility
Lipophilicity.

These dictate the ability of a molecule to pass through the cell wall

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14
Q

Is solubility always related to water?

A

Yes

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15
Q

Why can the majority of drugs be ionised in an aqueous environment?

A

The majority of drugs are weak acids or weak bases

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16
Q

Why is the unionised form of the drug significant?

A

It is more lipid soluble than ionised species and can passively diffuse across cell membranes more easily.b

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17
Q

What is the major limitation of lipski’s rule of 5?

A

It only describes the ideal criteria for drugs passing through the cell via passive diffusion
E.g. Erythropoietin is a successful drug but does not comply with lipski’s rule of 5. This is because it violates passive diffusion and utilises active uptake of the cell

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18
Q

What is the effect of pH on drug solubility ?

A

Acidic or basic pH either enhances or reduces the ionisation of the drug according to the henderson hasselbach equation.
This will influence drug solubility and absorption through membranes.

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19
Q

Why is the pKa of a drug important?

A

It is an improtant parameter/descriptor regarding solubility and its ability to get through a neutral membrane

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20
Q

Why are mildly acidic functional groups (e,g, alkyl carboxylic acids pH 5-6 and 4-5) used?

A

We can use these to make salts

The pKa is close to the pH of most fluids in the body

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21
Q

What are really strong bases such as guanidine with a pH of 10-11 used for?

A

To tag compounds suck in malaria

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22
Q

Why is pH of body compartments important?

A

We need the functional groups in the rug to allow molecules to be partly ionised and a partly neutral at that pH for solubility and permeability

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23
Q

Is aspirin more ionised or neutral in the stomach?

A

Neutral. The presence of strong acid such as HCl will push the equilibrium to the left, so most of the acid is electronically neutral

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24
Q

What form of chlorpromazine (weak base) exists in the intestine?

A

The non ionised form predominantly exists in the intestine

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25
Q

Why should acidic and basic functional groups not be combined in a drug molecule?

A

The drug molecule will be complicated by internal salt formation.
At midrange pH they will have very poor solubility like in amino acids.
At low pH, cationic species and at high pH, anionic species have better solubilities.

These variations in solubilities alter the therapeutic effectiveness of the peptide and influence design of dosage forms

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26
Q

What are the other processes involved in oral abosrption?

A

Disintegration of drug product into small particles and release of drug

Dissolution of rug relies on particle size of drug product and physicochemical properties of drug - e.g. Ionisation

Sometimes neither disintegration nor dissolution are complete. Leading to reduced bioavailability

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27
Q

What are the advantages and disadvantages of intravaneous administration?

A

+ absorption factors are avoided
+ achieves desired concentration obtained with accuracy and immediacy

  • has its own required properties like water solubility and precipitation blood constituents
  • it is a more invasive route for the patient than the oral route
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28
Q

How can the drug absorption be predicted?

A

Using lipski’s rule of 5
Calculating the solubility at various pH, predicting pKa
Assess its membrane permeability using caco-2 or MDCK

29
Q

What is log p?

A

The intrinsic lipophilicity- affinity of a whole molecule for a lipophilic substance

30
Q

How is log p measured?

A

By drug distribution in a biphasic system, either liquid liquid (partition coefficient)
Or solid liquid (Rf on reversed phase HPLC)

31
Q

What is the most commonly used organic solvent for the determination of log P?

A

N-octanol.
The aqueous phase is either water or a phosphate buffer.

A higher value of log P indicates compound will readily diffuse into membranes and fatty tissue i.e, hydrophobic

Low value of log P indicates that the compound is reluctant to enter the lipid membrane i.e. hydrophilic

32
Q

How is MDCK used to determine membrane permeability

A

Monolayers of cells are used to estimate rug absorption rates
This can be used in an HTS environment to rank the compounds by oral absorption profile

Yields apparent permeability

If transport from basolayer all side to apical side is higher than A to B then this implies presence of efflux pumps which can be confirmed by re assay in the presence of inhibitors

33
Q

What are the advantages of using Caco-1 or MDCK to determine membrane permeability?

A

It is automatic
Chemicals are in solution/ buffer
Can detect where the drug goes over a period of time
Use HPLC or other analytical techniques to see whether molecules pass through
Can start at the bottom to measure how much goes up the cell

34
Q

What is the bottom of the container for Caco-2 or MDCK assay?

A

A layer of cells

35
Q

How can drug water solubility be improved?

A

Salt formation
Incorporation of water solubilising groups into structure
Disruption of molecular planarity and symmetry
Drug delivery systems
Formulation - not covered in this course

36
Q

How does salt formation improve drug water solubility?

A

Improves solubility of acidic and basic drugs as the salts dissociate in water to produce hydrated ions.

E.g. Acidic drugs are often paired with metal ions or amine salts.
Sodium or potassium salts are very common
E.g. Fusidic acid diethanolamine which is an antibacterial eyedrop for conjunctivitis. Has a mid strength carboxylic acid which is more acidic than normal. So it can be paired with an amine salt

37
Q

What are basic drugs paired with?

A

Organic or mineral acids
E.g. HCl salts are very common
Lactate and tartrate salts common too. E.g. Chlorpromazine embonate which is bigger on its own as an alkaloid, but tasteless with a salt

38
Q

What other factors affect salt solubility?

A

Crystalline polymorphism. Where different crystalline forms of the same drug have different packing forms which later their solubility

Particle size. Decreasing size of crystals increases solubility. Below a variable minimal size, solubility will decrease.

Common ion effect where increased concentration on right hand side of equilibrium leads to left hand shift in equilibrium to lower solubility product. Some drug HCl salts actually precipitate in the stomach due to common ion effect

39
Q

What are some uses for water insoluble salts?

A

Some dissociate in small intestine to liberate component acid and base
E.g. Erythromycin stearate

Others act as drug depots e.g. Penicillin G procaine IM

40
Q

How does the incorporation of water solubilising groups increase drug water solubility?

A

Incorporation of polar groups in the structure of a compound will normally result in a more water soluble analoge

41
Q

What kind of water soluble groups are introduced?

A

Acidic or basic groups particularly useful because these groups can be used for salt formation resulting in a wider range of dosage forms
E.g. Doxylamine which is an antihistamine and hypnotic. The alkyl amine group is more solbule.

42
Q

Why do modifications of the drug need to be tested

A

To make sure it still retains its biological effect and to check the changes are desireable

43
Q

How does disruption of molecUlar planarity and symmetry increase the drug water solubility?

A

According to yalkowskys general solubilisation equation, the solute in water is dependent on the ability of the solute to interact with water and the crystallinity of the solute

So disrupting the planarity and symmetry decreases efficiency of crystal packing resulting in decreased melting point and increased solubility

44
Q

What are examples of disrupting molecular planarity?

A

Removal of aromaticity
Increasing dihedral angle (by adding methyl groups which cause steric clash)
E.g. Integrin dual antagonists for the treatment of acute ischaemic disease

45
Q

How do drug delivery systems increase drug water solubility?

A

Drug delivery systems not only enhance drug solubility
They also

Protect drug from premature degradation
Function as a sustained release system
Increases targeting of drug to diseased tissue

46
Q

What are examples of rug delivery systems?

A

Liposomes
Micelles
Polymer or antibody drug conjugates

47
Q

What are surfactants?

A

Phospholipids which lower the surface tension of water
Contain both hydrophilic and hydrophobic groups and dissolve in both polar and non polar solvents
Frequently used to prepare solutions of compounds that are in solbule or sparingly soluble in water

48
Q

How do surfactants form micelles?

A

When the CMC is exceeded, surfactants will preferentially form micelles.
The shape of the micelle depends on the concentration of the surfactant.

At concentrations just above CMC, the micelles are spherical.
As concentrations increases, micelle changes to cylindrical, lokinar and other forms

49
Q

How can drugs be incorporated into micelles?

A

Drug incorporation into micelles or liposomes can solubilise water in soluble drugs.
Non polar compounds accumulate in the hydrophobic core whee water in soluble compounds are orientated within their polar groups towards the surface

50
Q

What are liposomes?

A

Spontaneously formed spherical bilayer aggregates of phospholipids. They are surrounding an internal core of water

E.g. Phosphatidylcholine, a lethicin

51
Q

What are cyclodextrins?

A

Family of cyclic oligosaccharides which are structurally characterised by glucose units in classical chair conformation linked by α1-4 bonds. The most common are α, β, γ, and σ

52
Q

What do cyclodextrins do?

A

Form inclusion complexes with drugs
They have an outer hydrophilic surface
Inner hydrophobic surface
And form a 1:1 host guest ratio though other ratios are also possible

53
Q

What are the issues with cyclodextrins?

A

Di-O-methyl β CD had a strong affinity for cholesterol and is haemolytic
2-hydroxypropyl-β-CD is a very useful solubilise and increases the solubility of progesterone by 88 x in a 1.5% solution

54
Q

What are antibody drug conjugates

A

A drug e,g, cytotoxic agent, is fused onto an antibody via a linker.
The antibody is specific for a tumour associated antigen which has restricted expression on normal cells
The cytotoxic agent is designed to kill target cells when it is internalised and released
The linker is cut by enzymes in the anticancer cell which releases the cytotoxic agent

55
Q

What are the problems with antibody drug conjugates?

A

There is sometimes not enough difference between surface anticancer cells and normal cells -> reduced selectivity -> lots of side effects

56
Q

What is the mechanism of ADCs?

A 
ADC is in plasma
Binds to receptor of tumour cell
ADC-receptor complex is internalised. I.e. It is pulled inside the cell
Cytotoxic agent is released
Tumour cell undergoes apoptosis
57
Q

What are advantages of using drug delivery systems?

A

Enhanced drug solubity
Rates of hydrolysis and oxidation may be reduced thus improving stability of some rugs
Function as sustained release system
Increased targeting of drug to diseased tissue

58
Q

What are the disadvantages of drug delivery systems

A

Absorption and hence activity is dependent on being released from micelle and liposome
Surfactants can irritate mucous membrane and be haemolytically active
Some compounds may decompose more rapidly when incorporated into a micelle

59
Q

What are xenbiotics?

A 
Drugs
Food constituents
Food additives
Agrochemicals
Pollutants
Industrial chemicals
60
Q

What was the first human metabolism study?

A

Alexander Ure observed conversion of benzoic acid to hip uric acid.
He later proposed the use of benzoic acid for the treatment of gout

61
Q

What are the sites of drug metabolism?

A 
Liver
Lungs
Kidney
Brain
Intestine
62
Q

What are the different characteristics of metabolites?

A 
Inactive
Polar
Water soluble
Excreted more easily
Some may be more active than original drug
63
Q

Are all metabolic reactions enzyme catalysed?

A

Most are, but some are not

64
Q

What is the first pass effect?

A

Drugs absorbed from GIT must pass through liver to reach the general circulation. As a result of metabolism in GIT, a fraction is lost.

65
Q

Why does the body metabolise?

A

Most drugs and xenbiotics are lipid soluble

The aim of metabolism is to produce compounds with increased water solubility

66
Q

Why is a higher water solubility aimed for in metabolites?

A

Higher water solubility facilitates excretion primarily in the urine or in some cases into the bile
Metabolism into water soluble compounds stops reabsorption of drug molecules from urine through renal tubular membranes back into plasma

67
Q

How is the first pass effect avoided?

A

By changing the route of administration
E.g. IV, IM, SC, or topical application

However not all drugs can be administered by an alternate route so we would need to alter the drug structure to minimise FPM

68
Q

What is the significance of stereochemistry of drug metabolism?

A

Some enzymes are stereospecific and altered stereochemistry can produce different substrates.

enantiomers may be metabolised by different routes, producing different metabolites e.g. S warfarin metabolite has the OH , R warfarin metabolite does not.

69
Q

What is the example of an inert enantiomer converted into the active enantiomer?

A 
R ibuprofen (inactive) is metabolised into s ibuprofen (active) 
If a racemic mixture is adminstered, 70:30 mixture of S:R is excreted
70
Q

What are the secondary pharmacological implications of metabolism?

A

Metabolites may be pharmacologically inactive
Or they can be active and
Exhibit a similar activity to the drug e.g. Diazepam
Exhibit a different activity to the drug E.g. Iproniazid (antidepressant) is metabolised to isoniazid (anti TB)
Be the sole cause of activity e.g. Prodrugs

Chem390 (21 decks)

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