ADME flashcards

ADME phases:

• absorption, distribution, metabolism and excretion

• AMDET includes toxicology

• pharmacokinetics

reasons for conducting ADME

• predicting if correct properties for use eg dosing frequency

• determining initial dose

• determining if drug like properties

drug like properties

• structural

  • hydrogen bonding, polar surface area, lipophilicity, shape, MW, reactivity, pKa

• physiochemical

  • solubility, permeability, chemical stability

• biochemical

  • metabolism, protein and tissue binding, transport

• PK and toxicity

  • clearance, half life, bio

Which drug discovery stages is ADME implemented in?

• target identification

• hit identification

• lead identification

• lead optimisation

What are exceptions to the lipinskis rule of 5 for good absorption/permeation?

substrates for membrane transporters

why is solubility of drugs important

• drugs must be in solution before absorption can occur

• movement of unchanged drug from site of administration to systemic circulation is crucial for absorption

• low lipid solubility = poor absorption = low oral bioavailability

bioavailability (F) definition and equation

• fraction of administered dose which reaches the systemic circulation and is active at intended drug site

• F = AUCroute / AUC IV

which route has the highest bioavailability ?

• IV route

• F=1

examples of physiological barriers which impact bioavailability

• liver

• blood brain barrier

• intestinal mucosa

explain the low availability from the stomach and liver

Ø parietal cells secrete HCl

Ø chief cells secrete digestive enzymes

Ø presystemic extraction by the enterocytes and/or liver

Ø efflux by P-glycoprotein

p glycoprotein

• ABC transporter superfamily

• responsible for multi drug resistance in cancer cells

where is p glycoprotein found

• in high concentrations of apical surface of epithelial cells in intestine, liver, kidney and BBB

transport across the intestinal mucosa depends on what factors?

size, charge, lipid solubility, concentration gradient

ABC transporters

• involved in active transport

• contains nucleotide binding domains and transmembrane domains

partition coefficient - P definition and equation

• measure drugs lipid solubility

• indicates ability of drug to cross cell membrane

• P = concentration in organic solvent / concentration in aqueous

P values indicate what

• lipid solubility

• P > 1 - lipophillic

• P < 1 - hydrophilic

in vitro permeability methods

• cell based - caco-2 cell layer method

• cell free permeation methods - IAM HPLC, PAMPA

• organoids

• in silico

where does the highest absorption occur and why

• small intestine rather than the stomach

• due to increased surface area

caco-2 cell layer method

• prepare human cell line of colon

• drug molecules are added to apical side

• measure the time and concentration of molecules which are absorbed across the caco-2 cells to the basolateral side

advantages of caco-2 cell layer method

• can measure passive diffusion, active and efflux

• good prediction of absorption

• has microvilli + p-glycoprotein

limitations of caco-2 and alternatives

• expensive

• cell free permeation methods - IAM HPLC, PAMPA

• but can only mimic passive diffusion

define distribution

• reversible transfer of drug between blood and various tissues

what factors affect the extent of distribution

• molecular size

• lipid solubility

• pH partitioning

• tissue perfusion

• protein binding

• tissue binding

• capillary permeability

• disease state

• drug formulation

problems if large molecular size

• poor absorption and distribution

• remains in the vasculature

Describe the relationship between particle size of a compound and its oral bioavailability. (1 mark)

• larger the particle size

• the less the bioavailability

perfusion of tissues and accumulation relationship

• highly perfused tissues accumulate drugs more rapidly

• leads to higher Vd

order of tissue perfusion from highest to lowest

• lung

• kidney

• liver

• heart

• gi tract

• brain

• adipose

apparent volume distribution Vd

• hypothetical volume that would contain the total body content of the drug Q

  • at a concentration equal to that present in the plasma at steady state

  • relates the amount of drug in the body to the blood concentration

calculation for apparent volume of distribution Vd

how to calculate Vd from a graph

• extrapolate to find C0 before elimination

• dose / this value

• make sure units are in L

plasma protein binding and Vd. give relationship and example

• warfarin has a lower Vd because it is tightly bound to plasma proteins rather than tissues

• lower the Vd less binding of drug molecules to tissues and more to plasma proteins

what factors does Vd depend on

–binding of drug molecules to plasma proteins (Vd is low)

–binding of drug molecules to tissues (Vd is higher), e.g. **more lipid soluble drugs

Vd size and [blood]

• drugs with small Vd will achieve larger [blood]

• drugs with large Vd will achieve lower [blood]

first pass mechanism

• 30% will be absorbed into enterocyte uptake

  • this is due to gut lumen and intestinal metabolism

• portal vein to liver then 15% will make it into the systemic exposure

  • CYP450 metabolism

How do drug molecules move around the body?

• bulk flow (i.e. in the bloodstream, lymphatics or cerebrospinal fluid, or during passage through the gastrointestinal tract)

• diffusion (i.e. molecule by molecule, over short distances).

3 main ways (+1) small molecules cross cell membranes

• by diffusing directly through the lipid;

• by combination with a solute carrier (SLC) or other membrane transporter;

• by diffusing through aqueous pores formed by special membrane glycoproteins ( aquaporins ) that traverse the lipid;

• further, small quantities of macromolecules may cross cell barriers by pinocytosis – ‘cell drinking’

ion trapping

• ionisation and permeability affect rate of absorption and distribution

• ions will accumulate across membrane due to differences in pH and ion charge

• quantified by fura-2

why do large ion gradients not reach theoretical values

• small permeability changes will have big effect on conc

• body compartments rarely reach equib

• bulk flow reduces conc gradeints below theoretical values

pH and accumulation

• weak acids accumulate with areas of high pH

• weak bases do the reverse

What does amount of drug bound to protein depend on

• the concentration of free drug

• its affinity for the binding sites

• the concentration of protein

Which of the following has the most impact on the bioavailability of a small molecule drug?

• A.Displacement of plasma protein binding by competing drugs

• B.The partition coefficient of the drug

• C.Its rate of diffusion through aqueous pores

• D.The diffusion coefficient of the drug

• E.The pH of the compartment

B

Which of the following is NOT a major factor of consideration when choosing the most effective route of administration of a drug?

D

• occurs irrespective of initial route of administration