W24&25 Integrated Pharmacokinetics Flashcards
Pharmacokinetic graph:
Y axis- Conc of drug in the body of plasma
X axis- Time following administration of a single dose
Initially, rate of drug absorption > Rate of drug elimination (a-b)
Then, rate of drug elimination > Rate of drug absorption (c-d)
*refer to ppt to see visual
What is bioavailability (f)?
F= fraction of administered dose of drug which reaches system circulation (intact)
- What is partitioning
- What is pH-partition theory?
- Process of molecules distributing
(partitioning) themselves between two domains - Brings together the Henderson-Hasselbalch equation and partitioning to explain absorption
of drugs
What is a Salt factor?
Considers the fact that the drug may be in the
form of a salt or a prodrug, e.g. an ester
Terminology: area under the curve (AUC)
This is measured to see which drugs have the best/fasted effect.
- AUC: total exposure of the body to a drug over a period of time
- AUC units in this example would be: ug h mL-1
(or ug h/mL-1)
Pharmacokinetics Vs Pharmacodynamics
Pharmacokinetics- What the body does to the drug Pharmacodynamics - What the drug does to the body
Journey of a drug reaching a target site
What are the direct and indirect routes?
Direct: e.g skin, eye, gut, nose, lungs and others
Indirect: via blood, e.g heart, kidney, liver & others
(dilution of dose, tissue deposition, metabolism &
elimination)
What are the considerations for drug administration?
- Parenteral Vs Enteral/Local Vs. Systemic effect
– Drug need to act locally (ointments, creams, eye drops and others)
– Drug’s physical/chemical characteristics suggest to avoid parts of G.I.
tract and/or liver (avoid first pass metabolism, alternative routes like,
inhalation, nasal, sublingual, rectal, skin; inhalation of volatile
anaesthetics)
– Desired drug kinetics, rapid/slow access/ fast or sustained delivery
(insulin formulation, rapid, slow and sustained)
– Ease of administration (paediatrics, geriatrics and immobile patients)
– Adverse/ toxic effects
What is the area between the ineffective range and toxic range of drugs?
The therapeutic range/window
Why is IV the best form of drug administration?
- Drug is delivered rapidly into plasma, and reaches steady-state concentration (i.e remains within therapeutic window for duration of treatment)
Whereas the ADME of other drugs follows a time-dependency
Usual drug pharmacokinetics may not be true if: (3)
*The drug effect is mediated through a metabolite
* The drug effect is irreversible
* Follow different kinetics in the target compartment
(different from blood)
What is the Significance of quantitative pharmacokinetics? (3)
- Dosing regimen: Understand person and conditions specific drug behaviour
- Empirical measures: Handling of drugs by the human body
- Track & trace: Drug disposition in the body (after
administration)
What are the different routes of administration which lead to absorption of a drug? (3)
Intravenous/IV- Blood
Oral- Gut
Intramuscular/IM- Muscle
What is important to consider for drugs reaching the target via blood/plasma (systemic circulation)
The magnitude of drug effect is associated to (drug) available in the plasma/blood
(This is why it is important to create a drug which works in the therapeutic range)
Where do drugs need to be delivered to?
What are the mechanisms of drug delivery?
Gut/mucosal membrane
Passive diffusion and Active diffusion
Why is passive diffusion important in drug delivery?
– Major mechanism of drug delivery
– Depends on the ability of drug (physiochemical characteristics)
crossing lipid bilayer membrane
Rate of diffusion
-surface area
-thickness of membrane
-molecular size & lipid solubility (diffusion constant)
[D] amount transfer
- Transfer rate
- Residence time at
membrane
Why is active diffusion important in drug delivery?
– Require transporter/carrier for the uptake of drug across cell membrane
Low lipid soluble (hydrophilic) drugs use transporters
Organic anion transporters (OATs)
Organic cation transporters (OCTs)
(also covered in urinary system lectures)
How are drugs able to pass through the cell membrane?
Un-ionised (only) drugs will cross lipid bilayers by passive diffusion
What are the factors affecting ionisation?
– pH (i.e. concentration of H+ ions)
– pKa of drug
(pH at which 50% of molecules are in each state)
What are the optimum pH in the Mouth, Stomach and Small Intestine?
Mouth- pH 7.4
Stomach- pH 1.5
Small Intestine- pH 5.3
- The precise degree of ionisation will be determined by the pKa and the exact pH
What are the factors influencing GI absorption?
- G.I. motility
- G.I. secretions & enzymes
- drug-food/supplement interactions
What are the Advantages of G. I absorption (physiological)?
– Large surface area for passive diffusion
– Range of pH environments promote uptake of weak acids/bases
– Richly vascularised (high blood supply)
– Long tract and long dwell time
– Some active transport (e.g. Levodopa taken up by phenylalanine transporter)
– Small intestine is a major site for drug absorption
How is bioavailability measured on a graph?
F= AUC of oral/AUC of I.V (for oral drug)
Time to peak (tmax): time required to reach maximum drug concentration in plasma (is a measure of rate of absorption)
What does the rate of absorption depend on?
Vascularisation of site of absorption
Characteristics of formulation/dosage forms
Lipid solubility of drug
pH of site of absorption
What is the definition of partitioning?
Partitioning is the distribution (or moving) of a substance between two immiscible phases
How is laboratory partitioning behaviour investigated using a separating funnel? (5)
- Immiscible liquids added to separating funnel
- Drug under investigation added to
the mixture - Separating funnel shaken (open tap regularly to release pressure build-up)
- Immiscible phases separated and concentration of drug in each liquid determined
- Partition coefficient is determined from these values
What is the partition coefficient equation (aka distribution coefficient)?
Partition coefficient (P) =Co/Cw
Where: Co is the conc. in the organic phase
Cw is the conc. in the aqueous phase
- P is the measure of relative affinity of the solute for an aqueous and a lipid phase at equilibrium – it will be constant
- Only applies to dilute solutions, i.e. ideal solutions
What is pH partition theory?
pH-partition theory states that the absorption of weak acids and bases is determined by the degree of ionisation, i.e. Henderson-
Hasselbalch equation
What is used as an expression as the range of the partition coefficients of common drugs is quite large?
- Often log10 P is used
- log P gives an indication of the
lipophilicity of a drug
What is the equation for partitioning of weak acids and bases?
P app= [HA]o/ [HA]w
Where is a weak base (drug) more likely to be absorbed?
In the small intestine as the pH is 5.5 and above
Pharmaceutical relevance of Partition theory
- Drugs typically need to pass several lipophilic barriers, e.g. intestinal membrane, cell membranes, blood-brain barrier etc. before they can exert an effect
- Aqueous solubility is also important as the drug molecule is typically required to be in solution for absorption to occur
- Balanced hydrophilic-lipophilic properties are required
- Log P is a useful measure of this balance
Based upon pH-partition theory only, which one of the following drugs will be absorbed to the greatest extent from the stomach (assuming pH 1.5)?
Amlodipine (weak base) pKa = 5.0
Salicylic acid (weak acid) pKa = 3.0
Ibuprofen (weak acid) pKa = 4.4
Ibuprofen as the difference between pKa and pH is almost 3 units
What are the pH-partition theory limitations?
- The situation regarding drug absorption from the GI tract is actually more complex
- The small intestines are better designed for absorption than the stomach
- Surface area of the small intestines is up to 200 m2 as a result of microvilli (large)
- Drugs have a longer residence time in the small intestines than the stomach
- Small intestines have an excellent blood supply
- This means that even drugs which are ionised can be absorbed to a considerable extent in the small intestines
- Metformin (a weak base) is almost entirely
ionised at the pH of the small intestines, yet
it is mainly absorbed in the small intestines - pH of the bulk gastro-intestinal fluid may differ from that at
the surface or within the epithelium, i.e. the local pH - Degree of ionisation is not the only determinant of
absorption from the GI tract - Other factors will include:
- Molecular weight
- Lipid solubility (log P often used as a proxy)
- Water solubility
- Binding to Ca2+, Mg2+, Al3+ present in milk, antacids etc.
- Ion-pairing
- Presence of active transport mechanisms
What is ion pairing?
- Ion-pairing is when oppositely charged ions are held together without the formation of a covalent bond
- The ion-pair behave as a neutral species and may be better able to permeate the gastric mucosa
Which substances move via active transport mechanisms?
- Ions (Na+, Cl–)
- Glucose
- Vitamins
- Amino acids
- These transport mechanisms require energy, i.e. it is not just passive diffusion
- This means that molecules may be absorbed even if they are ionised or highly hydrophilic
- Some drug molecules resemble vital compounds and may be actively absorbed by the same mechanisms
Melphalan is an anti-cancer drug indicated for several conditions including multiple myeloma
How does it work?
It is similar in molecular structure to phenylalanine and is actively absorbed in the GI tract
The body believes that it is the amino acid phenylalanine and so actively uptakes it into the bloodstream.
pH, partitioning and breastfeeding
Many drugs can distribute into breast milk and risk
inadvertent administration to infants
What are the advantages of breast feeding?
Milk readily available
Free
Sterile
Right temperature
Nutritional requirement
What 3 parameters determine the degree of drug
distribution into breast milk?
- pKa of drug (milk has a mean pH of 7.2)
- Degree of plasma protein binding
- Log P of drug (milk fat content varies from 4 – 9%)
What are M/P ratios?
Milk: plasma drug concentration ratios) are
published – ideally will be low, but also need to consider maternal dose, amount of milk drunk by the baby, toxicity
* BNF offers advice on prescribing to breast-feeding mothers
pH, partitioning and drug excretion
What is the pH range of urine?
What happens to ionised form of drug in the kidney?
- Ranges from 4-7.5
- In the kidney, unionised drug may partition from the blood (pH 7.4) passes through the lipid membrane then passes into the urine
- If urine pH favours the ionised (water-soluble) form of the drug then it is excreted in the urine
What happens to the unionised from of the drug in the kidney?
- If unionised form is favoured, the molecule may be reabsorbed back into the circulation by passing
back through the lipid membrane in Loop of Henle - Drug re-enters the circulatory system, free to exert its therapeutic action again
How can renal excretion of drugs be controlled?
By altering the pH of the urine with salt solutions, e.g. sodium citrate which is urine alkaliniser
- Acidic urine:
- Weak basic drugs are more likely to be ionised
- Decrease in re-absorption & increase in excretion
- Alkaline urine:
- Weak basic drugs are more likely to be unionised
- Therefore increase in re-absorption and decreases in excretion
Drug binding with plasma proteins
Drugs bind reversibly with plasma proteins
In general, the plasma protein-bound drug is inactive
The [free drug] determines the concentration gradient and the direction of diffusion (influx or efflux)
- [Free] or [bound] drug is in dynamic equilibrium
- High binding to plasma proteins- less available for target action
- One drug can displace other drug binding of other drug
- (Thermodynamic motion, collision; thermal energy dominate the electrostatic forces)
Reversible binding to plasma proteins
What do acidic and basic drugs bind to?
- Acidic (& neutral) drugs bind to albumin
(warfarin) - Basic drugs bind to β-globulins (quinine)
What factors influence the distrbution of drugs?
Barriers
- cell arrangements
-active transporters
- size and lipid solubility
Blood flow (how well the tissue perfused)
-High: heart, brain, lungs, kidney, glands
-low: skin, muscle
-negligible- bone, teeth, hairs, cartilage
Tissue accumulation (fat depots)
-Highly lipid-soluble drugs accumulate
acute- thiopental
chronic- xenobiotics, benzodiazepines
Possibility of redistribution of drugs
Influence kinetics
in summary; The blood supply, lipid solubility and tissue depots affect the kinetics of drug distribution
What is the Blood Brain Barrier?
Tight junctions, restricted access to
biomolecules
* Diffusion only possible for lipid soluble drugs
* The integrity compromised during meningitis (allowing access for antibiotics)
* Active transport possible (e.g. methylDOPA)
What is the Blood Placental Barrier?
Tight junctions, restricted access to biomolecules
* Lipid solubility and size of the drug determine the distribution to the foetus.
* Drug use in pregnancy: Risk-averse/toxic teratogenic effects during pregnancy and
neonatal toxicity during labour
Pharmacokinetics- Volume of Distribution
Where are drugs found in the body?
A. Drug bound to plasma proteins
B. Fat Depots
C. Fluid Compartments
▪ 40 liters total body fluids
▪ 15 liters Extracellular
▪ 25 liters Intracellular
▪ 3 litres Plasma (fluid)
▪ 12 litres Interstitial
▪ Includes cerebrospinal / matrix
▪ >90% as a gel
Pharmacokinetics- Volume of Distribution
Where are drugs found in the body?
A. Drug bound to plasma proteins
B. Fat Depots
C. Fluid Compartments
▪ 40 liters total body fluids
▪ 15 liters Extracellular
▪ 25 liters Intracellular
▪ 3 litres Plasma (fluid)
▪ 12 litres Interstitial
▪ Includes cerebrospinal / matrix
▪ >90% as a gel
Pharmacokinetics:
How do you calculate Vd (Volume of distribution)
What does it mean?
Vd= Total amount of drug (Q)/ Plasma concentration (Cp)
It indicates the theoretical distribution of drugs in various fluid and tissue compartments
Volume of distribution
The total amount of drug (Q) will vary with time due to elimination
- Vd > 40 litres: drug accumulation in tissues
- Vd < 10 litres drug restricted to plasma and interstitial fluid (largely)
What is bioavailability (F)?
F=fraction of administered dose of drug which reaches system circulation (intact)
What is Naloxone used for?
- Used to combat opiate overdose
- Rapid onset required
- Undergoes first-pass metabolism and so IV administration is used
What is first-pass metabolism?
- Drugs absorbed from the stomach, small
intestines and upper colon pass into the hepatic
portal system, then goes to liver - Some drugs are metabolised extensively through their “first-pass” through the liver
How is bioavailability determined?
Absolute bioavailability (F) is calculated by comparing the amount absorbed by one route, e.g. oral, to the IV route
- Most commonly derived through the production of blood plasma concentration–time curves after i.v. and oral dosing
- Samples of blood withdrawn from a patient/volunteer at time intervals after a dose is administered
- The same patient would have boththe i.v. and oral dose administered (at different times – “washout”
period) - Comparison is the made of the “area under the curve”
What could reduced bioavailability possibly be due to?
Incomplete absorption and/or first-pass
clearance
This would be repeated with several different
patients/volunteers
How do you calculate Bioavailabilty graphically?
AUC
1/2 (a+b) x h
What is Relative bioavailability (F rel)?
What is the calculation?
Relative bioavailability (Frel) is calculated by comparing the amount absorbed from a test formulation, e.g. an oral drug solution, to a standard formulation such as a tablet
F rel= AUC test/ AUC standard
F rel is often used to measure changes in formulation parameters, e.g. dosage form, excipients, processes
Bioequivalence
- Relative bioavailability is used to evaluate bioequivalence
(BE) of two products containing the same drug - BE studies are important when a generic equivalent of an
innovator product is launched - Pharmacokinetic studies to assess BE will investigate
parameters such as AUC, Cmax and Tmax
What is the Salt factor (S)?
The salt factor (S) or salt correction factor is the fraction of the dose (which may be in the form of a salt or ester) that is the active drug
The salt/ester does not contribute to the therapeutic effect
Multiply bioavailability (F) by S to get true value (true bioavailability)
Drug metabolism- First pass metabolism
Most common site of drug metabolism is liver and it is a significant problem for orally
administered drugs, as liver contains several drug-metabolising enzymes (DME).
These enzymes facilitate the chemical processes to make drugs more water soluble
GI contents are drained into the liver and so toxins are removed.
What are DME’s?
Examples?
Drug metabolising enzymes
DMEs
– Cytochrome P450
– Alcohol dehydrogenase (ethanol)
– Esterases
What are the phases of drug metabolism? (2)
– Phase I = oxidation, reduction, hydrolysis
– Phase II = conjugation
What is phase 1 of drug metabolism catalysed by?
Phase 1 is catalysed by Cytochrome P450 (Haem-containing mono-oxygenase enzymes)
– 74 CYP gene families and multiple substrates
– CYPs evolved to deal with environmental/nutritional toxins (e.g. plant alkaloids)
– Some drugs or foods can increase the expression of specific CYPs (phenytoin, broccoli)
– Some drugs or foods can inhibit the CYPs activity (grape fruit juice)
– Metabolites could be more active than the drug (pro drugs)
– Phase 1 requires Oxygen and NADPH
What does phase ll of drug metabolism consist of?
Phase II is conjugation, the addition of polar groups (to convert drugs to more water soluble, that could most readily be excreted by the kidney)
o OH (glucuronyl, methyl, sulphate)
o NH2 (glucuronyl, acetyl)
o COOH (glucuronyl, glycine)
-the most common phase II catalysis is by UDP (Uridine-diphosphate)-glucuronyl transferases (UGTs)
-UGTs are a superfamily of enzymes that catalyze the conjugation of glucuronic acid to molecules primarily to facilitate systemic elimination
Drug Excretion/Elimination
Water soluble molecules:
Urinary system (Kidneys)- Major site of drug eliminations (3 stages)
– Glomerular filtration: Passive removal of [free] drugs
– Tubular secretion: Active transport
– Reabsorption: depends on lipid solubility & pH
Drug Excretion/Elimination
Large molecule: Biliary system (entero-hepatic recirculation)
– Active transport of large molecule into bile (glucuronides)
– Excreted into gut
– Redistribution of molecules into liver
– Reabsorption can be blocked by activated charcoal (e.g. treatment method for drug poisoning)
Names of 2 types of transporters
Organic anionic and Organic cationic transporters
[Drug] in blood continually changes with time.
Rate of elimination is dependent on free drug concentration in the blood
[Drug]t= [Drug]0 . e-ktelt
Elimination measures (Half-life)
Half-life (t1/2) = time taken to reduce the plasma drug concentration by half from the administered [drug] or a time at which 50% of drug eliminated from plasma.
Half-life is calculated from the exponential curve (linear plot)
Slope of the log (best linear fit) = Kel
For drugs eliminated by first-order kinetics, half life is constant regardless of concentration
Elimination measures (Plasma clearance, CLp)
CLp is the volume of plasma (ml) that is cleared of drug in unit of time (min): e.g. xy ml/min
CLP= CL liver + CL renal
What is the definition of The volume of distribution (Vd)?
The amount of drug in the body to the concentration of drug in plasma
The highly plasma protein-bound drugs are less available for target action
True or False?
True
The most common site of drug metabolism is _______________, as it contains several drug metabolising enzymes
The liver
The drug transport across the blood brain barrier (BBB) and blood placenta barrier (BPB) are highly restricted is due to which of the following reason?
Continuous and highly tight junctions of the cell wall
Which of the following is the likely absorption process of a weak lipid soluble or hydrophilic drug
Active carrier-mediated transport
The enzymes like cytochrome P450 catalyse the chemical process in the liver to convert the drugs into what
Highly water-soluble drugs that can be excreted by the kidney
Which of the following cannot permeate cell membrane by passive diffusion?
Hydrophilic drugs
The main mechanisms by most drugs absorbed in the GI tract is by which of the following process?
passive diffusion
