ADME Overview Flashcards
What are Lipinski’s rule of 5
- More than 5 H-bond donors (sum of NH+ OH groups)
- More than 10 H-bond acceptors (sum of N + O atoms)
- Molecular weight is >500
- Calculated log P (cLog P) is > 5
How does Lipinkskis rule relate to absorption
- drugs that are well absorbed tend to follow the rule
-> means they have good oral bioavailability
What does drug absorption require
Solubilisation
Solubilisation
Drug moves from solid to solvated molecules.
-> when drug is solid molecules, its stacked up against each other. It needs to broken to individual molecule before absorption = requires solubilisation
What are the 3 factors that effect absorption
- Ionisation (pH)
- Hydrophilicity
- Molecular shape
How does ionisation (pH) affect absorption
Drug ionised = accumulate charge = promotes solvation by h2o
- charge might come from functional group.
- protonation of functional groups depends on pH medium
-> carboxylic acid - deprotonated = -ve charge
-> amines - protonated = +ve charge
How does hydrophilicity affect absorption
- h2o polar media, drugs that are hydrophilic are more likely to dissolve in polar media
- hydrophobic drugs are less soluble in water
How does molecular shape affect absorption
- flat drugs tend to be less soluble than drugs with non planar structures
-> because flat drugs are more likely to stack next to each other (need to individual drug molecule to be absorbed)
Examples of transport across membranes
- pinocytosis
- paracellular
- aquaporin
- lipid diffusion
- carrier
Pinocytosis
- Membrane fold upon itself
- cell membrane invagines and forms vesicles = which traps the drugs inside cell
Paracellular
Drugs that can move between cells
- small polar drugs
- some membranes are more permeable than others e.g. nasal epithelium more leaky than GI tract epithelium -> why some drugs are administered through nasal root canal
Lipid diffusion
Drugs move across cell membrane directly - diffuse across lipid
-> drugs must have hydrophobic nature
Aquaporin
Drugs that move through ion channels
Responsible for taking up h2o
The drug would have to be small uncharged solutes
Carrier
- proteins that have other biological function
- structural similarity to drug
- can be active/passive
Fick’s law - passive diffusion
Flux across membrane =
(C1-C2) X area / permeability thickness
Conc.: larger = larger flux of drug across membrane
Area; larger = greater total flux of drug across membrane
Thickness: thick = reduces total flux
Permeability
Ability of the drug to move across membrane
Permeability depends on
- solubility in membrane lipid
-> lipophilicity = promotes
-> charge - ionisation is pH dependent = inhibits (less likely permeable in lipid environment) - mobility in membrane lipid (diffusion coefficient) = how well drug can diffuse in lipid bilayer itself
- molecular mass - larger the drug = less permeable
Maximum absorbable dose =
S X ka X tsi X Vsi
S = solubility
Ka = rate constant for absorption across membrane (controlled by permeability of drug across membrane)
Tsi = transit time through small intestine (longer drug in SI = greater chance of absorption)
Vis = vol of small intestine (larger = more total drug = increase amount of drug that can potentially be absorbed)
- Alkaline (proton removed) pH in
- Acidic (proton added) pH in
- GI tract
- Stomach
Carboxylic acid: acidic = uncharged alkaline = charged
Amines: acidic = charged alkaline = uncharged
PH partition hypothesis
Uncharged molecules (unionised) are more likely to cross membrane -> lipophilic
PH trapping
accumulation of a higher concentration of a molecule across the cell membrane due to difference of pH across the cell membrane.
Drugs that are bases tend to be protonated in acidic pH
-> cause amine = +ve charge = charge in stomach = harder to be absorbed
Acidic drug trapped in urine so prevents reabsorption
Carrier-mediated transport is important. Can it be saturated
For movement across membrane when cell-cell junction tight/ has other barrier
Yes when drug conc. are high (with high dose)
Uptake and efflux regarding carrier-mediated transport
Uptake: helps drug to get into cell = promotes absorption
Efflux: helps drug pump out of cell = reduces absorption
An example of efflux pump
P-glycoprotein (encoded by MDR 1) in GI membrane - inhibits absorption by returning drug to GI tract
What are the factors that affect gastrointestinal absorption (7)
- Anatomical factors
- PH
- Permeability and solubility
- Binding to other material in GI tract
- Gastric emptying
- Metabolism
- Efflux pumps in membrane
How does anatomical factors affect gastrointestinal absorption
- stomach: small surface area
- small intestine:
-> microvilli = large surface area, for drug to be absorbed (where most drugs are absorbed)
-> higher permeability
-> good blood supply - large intestine = intermediate
How does pH affect gastrointestinal absorption
- stomach: acidic, varies along the GI tract - pH rises
- affects charge
- can cause drug hydrolysis in stomach
Drug hydrolysis in stomach
Certain functional group e.g. ester, catalysed by presence of acid.
Some drug are unstable in acidic pH - so needs enteric coats to protect them and allow them to pass through stomach
How does permeability and solubility affect gastrointestinal absorption
- for polar drug: a prodrug may render more lipophilic and increase absorption transit time, may become more limiting
- transit time may become limiting: small intestine (-4hrs) large intestine (-10-36hrs)
How does binding to other material in GI tract affect gastrointestinal absorption
Other drugs: e.g. cholestyramine
Metal ions EG Tetracycline and M2+
How does cholestyramine affect GI absorption
- drug used to treat elevated plasma cholesterol levels
- +ve charged resin and binds to bile acids.
- gall bladder secretes bile into SI. Bile completes with cholesterol = allows absorption of cholesterol
- when cholestyramine binds to bile acid - bile acid won’t be availed to bind to cholesterol therefore absorption of cholesterol reduced
How does tetracycline affect GI absorption
- Avoids taking with milk.
- can form complexes with metal ions. Complex gets charged therefore metals get charged.
- charge associated with molecule is likely to limit its membrane permeability
How does gastric emptying affect gastrointestinal absorption
- emptying of stomach speeds process to small intestine - favours absorption
- food delays emptying- especially fat
- exception: poorly soluble drugs - delay provides more time for dissolution
How does metabolism affect gastrointestinal absorption
- by gut flora (bacteria residue = can affect drug)
- in gut wall
->cytochrome P450
->monoamines oxidase - in liver: first pass metabolism
- metabolism may be inhibited by food e.g. grapefruit juice and Cyp3a4
How does the cytochrome P450 and monoamine oxidase affect gastrointestinal absorption
These enzymes catalyse metabolism of certain drugs.
If drugs gets metabolised before absorption = less drug available to be absorbed + total amount of drug that gets absorbed is reduced
How does grapefruit juice and Cyp3A4 affect gastrointestinal absorption
These would inhibit metabolism.
Consequence: more drug available to be absorbed = patients get higher conc of drug than expected
Can be good and bad (adverse effect)
How does efflux pumps in membrane affect gastrointestinal absorption
E.g. P glycoprotein
Prevents absorption of drug from GI tract
Pumps back out
What are the factors that affects absorption from intramuscular + subcutaneous sites
- capillary endothelium mor permeable than GI epithelium = easier transit to blood or lymphatic system
- if tissue has good local blood flow = facilitate + speed up drug absorption
Distribution
Transfer / movement of drug within diff compartments of body = reversible process
- Interstitial water -
- Transcellular water -
- Water between intercellular structure
- H2O move across cell and from blood to get into compartment
Distribution - expl on complexes and compartments
Drug can form complexes with protein (large)
- don’t move between compartments
For these drugs to move, it needs to dissociate
-> equilibrium between bound + unbound - generally unbound drug more within compartment
-> blood - brain barrier restricts access to CNS
Blood-brain barrier
Prevents water-soluble drugs from reaching CNS
- free movement of drug between compartments - blood + brain = which affects drug distribution
- substance required by CNS have specific transporters (e.g. amino acid)
- some drugs may be carried by these transporters (e.g. L-dopa)
Factors that affect distribution (2)
- perfusion limited
- permeability limited
Perfusion limited factor for distribution
- membranes present little permeability barrier
- particularly lipophilic drugs
- blood flows limits drug distribution to tissue
- drugs accumulation favoured in tissue with better blood supply
Permeability limited for distribution
- membranes present more permeability barrier
- e.g. polar drugs affected by charge, pH
- e.g. antibodies (large molecules)
- blood flow not limiting
(Drug don’t cross cell membrane readily, blood flow don’t control distribution of drug, permeability affects distribution)
What drugs may bind to
- blood cells
- tissue protein
- plasma protein
How does protein binding affect distribution
Limit/effect distribution of drugs in different compartments
Examples Plasma protein that affects distribution
- serum albumin - function: to transport lipophilic (which is bound) molecules around body = mostly acidic drugs
Limits because drug bound to serum not the target - a1-acid glycoprotein = mostly basic drugs
- lipoproteins
May contribute to retention in plasma = reduced distribution
Fraction unbound of drug is important factor for distribution as:
- only unbound drug exerts pharmacodynamic effect
- only unbound drug move between compartments
How does rate of dissociation affect distribution
- slow/irreversible dissociation equivalent to elimination
- rapidly dissociation - drug still available + protein acts as carrier
Rapid and slow distribution
- rapid (instantaneous) distribution = one compartment model
All tissues in body behave as 1 compartments so drug diffuse into all tissues at same rate
Drug = elimination - slow distribution = two compartment model
Distribution + elimination of drug from 1st compartment to 2nd. Then rapid decrease in drug concentration so only elimination at the end.
Elimination is made out of
Metabolism + excretion
Phase 1 and phase 2
Metabolism overview
Conversion of drug to another chemical
- usually more readily excreted
- less pharmacologically active
Major site of metabolism- liver
Some drugs may not undergo phase 2
Some drugs may be excreted unchanged
Phase 1 of metabolism
Conversion to more reactive form to allow conjunction
- REDOX
- 95% reaction by cytochrome P450
-> contain heam /= Fe2+/3+ = undergo redox - allow enzyme to catalyse redox reaction on drug
-> several isoforms: CYP 3A4, 2D6
May oxidise several diff drug
May have overlapping specificities
- non cyp medicated: alcohol dehydrogenase, mono-amine oxidase - enzymes that can catalyse metabolism
Factors to consider in phase 1 of metabolism that could affect it
Interactions with other drugs and food
Phase 2 of metabolism
- hydrophilic group gets conjugated to drug molecule to increase solubility
After conjugation: more soluble + less reactive = less harmful
E.g. glucoronic acid, glutathione, sulfate
Excretion
Irreversible removal of drug from body
Routes of excretion
- urine
- bile: (to faeces)liver ca excrete bile into SI to absorb cholesterol
- sweat
- exhaled breath
- milk: drug crosses tissue barrier and into milk, potential problem if mother is breastfeeding
What are the 3 processes involved in renal excretion
- Filtration in renal corpuscle
- Active secretion in the tubule
- Reabsorption in the tubule
Filtration in renal corpuscle
- not if bound to plasma protein
- measure with creatine or insulin (no tubular secretion or reabsorption
- GFR - 120 ml min-1
Active secretion in the tubule
- active transport
- ‘non-specific’ : transporters for anions and cations
- saturable:because they are protein
- free drug not plasma protein bound drug
Reabsorption in the tubule
- physiologically: for recovery of glucose, vitamins etc - active transport
- drugs - passive diffusion
- pH dependent - charge
- lipophilic drugs - good reabsorption
Renal excretion overview
- polar drugs may be secreted into urine charged
- lipophilic drugs undergo phase 1 + 2 metabolism to render them more polar = more soluble
By:
-> Facilitates secretion (increase concentration of free drug, reduced serum protein binding)
-> reduces tubular reabsorption
Renal excretion equation
= glomerular filtration + tubular secretion - tubular reabsorption
Tubular secretion
- drug more polar by adding hydrophilic moieties - inhibits it
- reabsorption of drug from kidney tubules back into capillary
Biliary excretion
- active secretion into bile duct
- polar, large compounds only
- possibility of enterhepatic recycling
Or drug passes through SI without undergoing absorption - drug eliminated into faeces
