2 ADME overview Flashcards
Absorption
Drugs are broken down into single molecules to get absorbed
Absorption - Lipinski’s rule of 5.
Oral absorption is likely to be poor for a molecule if (Adv. Drug Del. Rev. 23:3 (1997)):
•there are more than 5 H-bond donors (sum of NH and OH groups) •there are more than 10 H-bond acceptors (sum of N and O atoms) •the molecular weight is >500
•the calculated log P (cLogP) is >5
What does absorption require..
• Absorption requires solubilization!
– ionisation (pH), hydrophilicity, molecular shape
» polar drugs usually more soluble
– solid drugs need to dissolve before they can be absorbed – rate of dissolution can limit rate of absorption
Drug absorption routes
Pinocytosis (membrane folds in upon itself and captures the drug and incorporates it into the cell)
Paracellular (between different cells)
Lipid diffusion (diffuse across lipid, drug must be hydrophobic
Aquaporin (uncharged, taking up water, very small channel, drugs must be small)
Carrier (primarily proteins with another biological property, can be active or passive, can be saturated, uptake or efflux promote or reduce absorption
Paracellular diffusion
• Between cells
• Usually only small (Mr < 350) polar drugs
• Some membranes are more permeable than others tight junctions
– eg nasal epithelium more “leaky” than GI tract epithelium – eg very tight junctions in blood brain barrier
Passive diffusion through lipid
Permeability is dependent upon
– solubility in membrane lipid (estimated by oil:water partition coefficient)
» lipophilicity
» charge - ionization is pH dependant
– mobility in membrane lipid (diffusion coefficient)
– molecular mass (reduces permeability)
Lipophilicity controls..
passive diffusion
Passive diffusion through lipid - Fick’s law
Flux across membrane
= (C1-C2) x Area x Permeability / thickness
Flux across membrane means how many drug molecules are moving across the membrane per unit time
Conflict
- Polar promotes absorption as it makes drugs more soluble
- Lipophilicity promotes absorption as it makes drugs more permeable.
Absorption is controlled by both lipophilicity and polarity.
Have to balance lipophilicity and polarity
Polar enough to pass through water and lipophilic to pass through membrane
What is a polar drug
charge unevenly distributed
Factors that determine the max amount of drug that can be absorbed
- Solubility
- Rate constanst for absortption across the membrane
- Time it takes for the drug to move through the small intestine
- Volume of small intestine
pH trapping
uncharged molecules more likely to cross membrane.
Drugs have functional groups which have a certain pka, this determines the ph at which they get protonated. Charge on the molecule depends on pH and pKa
Carrier-mediated transport
– active or passive (“facilitated diffusion”)
– can be saturated!
– Important for drug movement across » Blood-brain barrier
» Gastro-intestinal tract
» Renal tubule
» Biliary tract » Placenta
– Uptake and efflux - promote or reduce absorption
» Efflux pumps eg P-glycoprotein (encoded by MDR1 gene) in GI membrane inhibit absorption by returning drug to GI tract
Aquaporins
- Transport water and small uncharged solutes across membrane
- Responsible for reabsorption of water from renal tubule -Discovery →Nobel prize 2003
Factors affecting gastrointestinal absorption
Anatomical factors:
- stomach has small surface area (~1M2)
- small intestine has large surface area, microvilli (~ 200 M2), higher permeability, good blood supply,
- large intestine is the intermediate
pH:
– varies along GI tract
– affects charge, R-CO2H ↔ R-CO2-
– can cause drug hydrolysis in stomach
Permeability and solubility:
– for polar drug, a prodrug may render more lipohilic and increase absorption
– transit time may become limiting: small intestine (~4 hrs), large intestine (10-36 hrs)
Binding to other material in GI tract:
– other drugs eg cholestyramine
– metal ions EG Tetracycline and M2+
Gastric emptying:
– emptying of stomach speeds passage to small intestine and hence favours absorption
– food delays emptying – esp. fat
– exception – poorly soluble drugs – delay provides more time for dissolution
Metabolism: – by gut flora, in gut wall Cytochrome P450 and Monoamine oxidase – in liver – first pass metabolism – metabolism may be inhibited by food – » eg Grapefruit juice inhibits Cyp3A4
Efflux pumps in membrane:
– P glycoprotein can prevent absorption of drug into circulation
Subcutaneous
Surface under the skin
Factors affecting absorption from intramuscular and subcutaenous sites
- capillary endothelium more permeable than GI epithelium – easier transit to blood or lymphatic system
- local blood flow is major factor
Distribution
The reversible transfer of a drug between different tissues in the body
Many drugs exert their effect in interstitial water or intracellular water
interstitial water
surrounds tissue cells
intracellular water
inside cells
blood brain barrier
Blood-brain barrier prevents water-soluble drugs from reaching the CNS
What is rate of distribution limited by?
Limited by either perfusion or permeability
• Perfusion limited
– membranes present little permeability barrier
– particularly lipophilic drugs
– blood flow limits drug distribution to tissue
– drugs accumulation favoured in tissue with better blood supply
• Permeability limited – membranes present significant permeability barrier – eg polar drugs affected by charge, pH – eg antibodies – blood flow is not limiting
Perfusion
Flow of blood through the body’s blood vessels
Distribution: protein binding
• Drugs may bind to:
– blood cells
– tissue proteins
– plasma protein
» eg serum albumin, (mostly acidic drugs)
» α1-acid glycoprotein (mostly basic drugs)
» lipoproteins
» May contribute to retention in plasma – reduced distribution
– “Fraction unbound” (of the drug) is the most important factor: » Only unbound drug exerts a pharmacodynamic effect
» Only unbound drug moves between compartments
– BUT : Rate of dissociation determines significance
» very slow/irreversible dissociation equivalent to elimination
» rapidly dissociation – drug is still “available” & protein acts as a “carrier”
Metabolism: overview
• Metabolism
– conversion of drug to another chemical
» usually more readily excreted
» often less pharmacologically active (but not always)
• Major site of metabolism – liver
• Phase I
– conversion to more reactive form to allow conjugation
• Phase II
– conjugation with another biomolecule to increase solubility to allow excretion
• Some drugs may be excreted unchanged
• Some drugs may not undergo phase II
Metabolism: phase 1
• Oxidation & Reduction
• 95% reactions by cytochrome P450 “Cyp” – contain Haem & Fe2+/3+ – several isoforms of Cyp: 3A4, 2D6 – each isoform: » may oxidize several different drugs » may have overlapping specificities
• Non Cyp mediated
– Eg alcohol dehydrogenase, mono-amine oxidase
Cytochrome P450 cycle
draw
Metabolism: phase II
- Conjugation with hydrophilic moiety
- eg glucoronic acid, glutathione, sulfate
UDP- glucoronide + Drug –>(UDP glucoronyl transferase) Drug-glucoronide
Glutathione + Drug –>
(Glutathione transferase) Drug-glutathione
After conjugation more soluble, less reactive and less harmful
Hydrophilic moiety
has strong affinity for water
Excretion
the irreversible removal of drug from the body
• Reminder: Elimination = metabolism + excretion
• Routes of excretion
– Urine
– Bile (to faeces; possibility of enterohepatic recirculation)
– Sweat
– Exhaled breath
– Milk
Processes involved in renal excretion
- Filtration in Renal corpuscle
– not if Mr> 20,000 not if bound to plasma protein
– GFR ~120 ml min-1
– Measure with creatine or inulin (no tubular secretion or reabsoprtion
2. Active secretion in the tubule – Active transport – “non-specific” - transporters for anions and cations – saturable – free not plasma protein bound drug
3. Reabsorption in the tubule – Physiologically – for recovery of glucose, vitamins etc - active transport – drugs – generally passive diffusion: – pH dependant – charge! – lipophilic drugs – good reabsorption
Renal Excretion equation
• Polar drugs may be secreted into urine unchanged
• Lipophilic drugs undergo phase I and II metabolism to render them more polar and hence more soluble
– facilitates secretion (increased free[drug], reduced serum protein binding)
– reduces tubular reabsorption
Renal excretion = Glomerular + filtration
Tubular - secretion -
Tubular reabsorption
