Lecture 4: ADME Flashcards
Absorption
Drug transfer from its site of administration to the general circulation
Distribution
Drug molecules carried by blood to site of action
Metabolism
Transformation from one drug product to anotehr
Excretion
Removal of the drug product from the body
What is the overall goal of drug therapy?
For the drug to travel from its site of administration to its target site at desirable concentrations and at desirable time frame
Local administration
The site of action is localized around the site of administration
Systemic administration
Site of action is far from the site of administration
Drug must be transported between the two sites via the bloodstream
Before the drug is absorbed through the GI walls, what should it be available as?
Molecules solubilized in the intestinal fluids
What do solid oral pharmaceutical dosage forms undergo disintegration followed by?
Dissolution before they are available for absorption
What do liquid oral pharmaceutical dosage forms undergo before they are available for absorption?
Dissolution
What is a common route of drug administration?
Extravascular (especially oral)
What is the optimum site for most drugs for drug absorption after oral administration?
Upper portion of small intestine or duodenum region
Where can drugs be absorbed and by what process?
Alimentary canal Sublingual Buccal GI Rectal absorption
By passive diffusion
What type of drugs can be absorbed by the stomach?
Fat-soluble, acid stable
What is efficiently absorbed already in the stomach?
Ethanol because it is completely miscible with water and easily crosses cell membranes
Colon anatomy
Lacks vili
Limited drug absorption
Lack of SA, blood flow
Viscous semisolid nature of lumen contents
Duodenal region anatomy
High SA
Large network of capillaries
Helps maintain concentration gradient
Gastrointestinal motility
- absorption window
- transit time of drug affected by many factors
- migrating motor complex during interdigestive (fasted state)
- irregular contractions followed by regular high amplitude contractions in fasted state
What is the duration of fasted state I and what are the characteristics?
30 - 60 minutes
- quiescence
What is the duration of fasted state II and what are the characteristics?
20 - 40 minutes
- irregular contractions
- medium amplitude
- bile secretion begins
- onset of gastric discharge of administered fluid of small volume usually occurs before particle discharge
- onset of mucus and particle discharge
What is the duration of fasted state III and what are the characteristics?
5 - 15 minutes
- regular contractions with high amplitudes
- mucus discharge continues
- particle discharge continues
What is the duration of fasted state IV and what are the characteristics?
0 - 5 minutes
- irregular contractions
- medium descending amplitude
What is the duration of the fed state and what are the characteristics?
As long as food is present
- regular, frequent contractions
- amplitude is lower than phase III
- 4-5 contractions/min
What is gastric emptying delayed by/
High fat meals
Cold beverages
Anticholinergic drugs
What does a delay in gastric emptying tend to slow?
The rate of drug absorpion
What drugs degrade if gastric emptying is delayed?
Unstable drugs
Liquids and particles are not retained in the stomach
How long are large particles (tablets and capsules) delayed for by presence of food in the stomach and why?
3 - 6 hours
Retained and subjected to more mixing and trituration until size is reduced
Indigestible solids empty slowly, mainly during interdigestive phase
Small intestine characteristics
- peristaltic movement (CNS)
- independent of solid particle size or fed status
- retention time is about 3 - 4 hours
- high SA
- gradient bacterial content duodenum-ileum
Large intestine characteristics
- takes 53 hours from time something is ingested by mouth until excreted in feces
- unabsorbed drug molecules spend 90% of time in large intestine and in rectum where absorption is minimum
- highest bacterial content (anaerobic)
Bioavailability
Rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action
Absolute bioavilability
Fraction of the administered dose which reaches the systemic circulation relative to an intravenous dose (F)
Bioavailability graph
Displayed by concentration time curve of the administered drug in an appropriate tissue system
What does the bioavailability data help determine?
- amount of drug absorbed from dosage form
- rate at which drug was absorbed
- duration of drug’s presence in biologic fluid or tissue
- relationship between drug blood levels and clinical efficacy and toxicity
FDA bioavailability requirements
- NDA
- abbreviated NDA
- supplemental application if there is a:
Change in manufacturing process
New indication for use of drug
New or additional dosage regimen for a special patient population
Parameters for assessment of bioavailability
- peak height concentration (Cmax)
- Time of peak concentration (Tmax)
- Area under the blood concentration time curve (AUC)
Cmax
- rates of absorption and elimination are equal
- Conventional dosage forms usually have one max
- amount of drug expressed as concentration in a specific volume of blood
MEC
Minimum effective concentration
Concentration must be achieved for the patient to exhibit adequate response
MTC
Minimum toxic concentration
Tmax
- reflects the rate of absorption from a formulation, which determines the time needed for the MEC to be reached and to maintain it
- changes in the rte of drug absorption change the values of both Cmax and T max
- when the rate of absorption is decreased, the Cmax is lowered and T max occurs at the same time
AUC
- Measure of the total amount of drug absorbed into the circulation following the administration of a single dose of drug
- equivalent doses of a drug, when fully absorbed, produced the same AUC
- two curves with different Cmax and Tmax may have similar AUC
If equivalent doses of drug in different formulations provide different AUC values then…
= differences in the extent of absorption
What are oral dosage strengths based on?
Considerations of the proportion of the dose administered that is expected to be absorbed
What is the absolute bioavailability following oral dosing compared to?
Intravenous dosing
Calculating F
Extent of availability is usually assessed by measuring AUC
AUCpo x Doseiv / AUCiv x Dosepo
When F is less than 1 what happens to oral doses?
Must be larger than iv doses to provide the same concentration of drug in the plasma
Consequences of low bioavailability
Gastroointestinal toxicity
As bioavailability worsens, the variability from patient to patient tends to increase
Factors influencing oral bioavailability
F = Fa x Fi x Fh
What does Fa stand for?
fraction of the administered dose that is not destroyed in the gut or lost in the feces
% of dose available to permeate gut wall
Factors influencing oral bioavailability
F = Fa x Fi x Fh
What does Fi stand for?
Fraction of the dose that escapes metabolism in the intestinal wall
Factors influencing oral bioavailability
F = Fa x Fi x Fh
What does Fh stand for?
Fraction of the dose that escapes metabolism on first-pass through the liver
Passive transport
- diffusion (no external energy)
- molecules diffuse randomly in all directions
- net diffusion from the high concentration side to low concentration side
- flux = rate of transfer
Fick’s law of diffusion
Molecules diffuse from a region of high concentration to a region of low concentration
Drug distributes rapidly into a large volume after entering the blood
Concentration of drug in the blood is low relative to the concentration at the site of drug absorption
Cgi»_space; Cp
Passive transport
dQ/dt meaning
Rate of diffusion
D is constant
Passive transport
P
Permeability coefficient
Passive transport
k
Lipid-water partition coefficient of drug
Higher K favors absorption
Drugs that are more lipid soluble have a larger value of K
Passive transport
A
Higher A favors absorption (duodenum)
Where does the most rapid drug absorption occur?
Duodenal area of the small intestine
PH-partition hypothesis
If the pH on one side of a barrier differs then
- Drug will ionize to different degrees on either side
- Total drug concentrations on the two sides will be unequal
- The side where the drug is more ionized will contain greater portion of the drug
Weak acid and absorption
Will be rapidly absorbed from stomach
Weak base absorption
Poorly absorbed from stomach
What are the rules for drug molecules that would improve the chance for oral absorption?
- molecular weight <500 Da
- Not more than 5 H bond donors
- not more than 10 H bond acceptors
- octanol-water partition coefficient, log P ,5.0
Rules are not applicable to drugs whose absorption involves transporters
After a drug is absorbed, how are the drug molecules distributed throughout the body?
Systemic circulation
What are dependent on the drug’s properties and individual patient characteristics?
Location extent and degree of distribution
Intracellular water volume
27 L
Interstitial water volume
12 L
Plasma water volume
3 L
Extracellular water volume
15 L
Blood water volume
4.5 - 5 L
Blood cell water volume
2 L
What does the passage of drug molecules across a cell membrane depend on?
Drug and cell membrane
Do hydrophoboic drugs or hydrophilic drugs diffuse more easily across cell membranes?
Hydrophobic
Do small drug molecules or large drug molecules diffuse more rapidly across cell membranes?
Small drug molecules
Hydrostatic pressure
Represents the pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue
Capillary hydrostatic pressure (CHP)
Pressure exerted by blood against the wall of a capillary
Drives fluid out of capillaries and into tissues
Interstitial fluid hydrostatic pressure (IFHP)
Opposes hydrostatic presse
Which is higher arterial CHP or IFHP?
CHP
Absorption of fluids by lymphatic vessels
Fluid moves out of the capillary and into the interstitial fluid
Osmotic pressure
Net pressure that drives the movement of fluid from the interstitial space back into the capillaries
Blood colloidal osmotic pressure (BCOP)
Pressure created by the concentration of colloidal proteins in the blood
Effect on capillary exchange accounts for the reabsorption of water
BCOP and interstitial fluid colloidal osmotic pressure
BCOP is always higher because interstitial fluid contains few proteins
Net filtration pressure (NFP)
Difference between CHP and BCOP
Hydrostatic or filtration pressure
At the arterial end, as the blood newly enters the capillary, the pressure of the capillary blood is slightly higher than that of tissue, causing fluid to leave the capillary and enter the tissues
Absorptive pressure
Venules have lower pressure than tissue fluids allowing the filtered fluid to return to the venous capillary
Drug affinity
Partitioning and accumulation of a drug in the tissue or organ
How is the time for drug distribution generally measured?
By the distribution half life or tie for 50% distribution
Rate of distribution relationship with Q
Increasing Q leads to decreased distribution time
distribution time relationship with V
Increasing V leads to increased distribution time
What is the accumulation of drugs in the tissues dependent on?
Blood flow
Affinity of the drug for the tissue
Affinity to tissues may be due to
Solubility Binding to tissue proteins Low binding to plasma proteins Chelation Active transport Complexation with cellular DNA
Volume of distribution (VD)
Concentration of drugs in the plasma or tissues depends on the amount of drug systemically absorbed and the volume in which the drug is distributed
True volume is not known, just estimated
Drugs with large Vd
Dispersed or distributed to extravascular tissues
Less concentrated intravascularly
What can lead to high Vd?
Factors leading to high affinity to peripheral compartment and low affinity to central compartment
Solubility Transporters Peripheral metabolism Tissue binding Low plasma protein binding
Vd equation
Amount of drug added to system/ drug conc in system after equilibrium
What is the tissue drug concentration influenced by?
Partition coefficient
Tissue protein binding
Drugs with high Vd and affinity and albumin
Generally have high tissue affinity or low binding to serum albumin
Vd and hydrophillic drugs
Polar or hydrophilic drugs tend to have Vd similar to the volume of extracellular water
Applications of Vd
- anticipate initial drug plasma concentration
- estimate residual amount of drug in the body
- calculate doses/loading doses
- predict fluctuation of plasma concentrations in a multiple dosing regimen
- anticipate usefulness of dialysis as a detoxification procedure
Where is the principal sit of metabolism?
Liver
Mixed-function oxidases (MFOs)
Enzymes responsible for oxidation and reduction of drugs and certain natural metabolites
What do MFOs contain?
Constitute electron transport system NADPH Molecular oxygen CYPs Phospholipid
CYPs
Heme protein
Iron protoporphyin IX as prosthetic group
Responsible for >70% of drugs
Major source of drug-drug and drug-food interactions
Prodrugs
Inactive
Must be biotransformed in the body to metabolites that have pharmacologic activity
Purpose of prodrugs
Improve drug stability
Increase systemic drug absorption
Prolong duration of activity
Phase I reactions
Asynthetic reactions
Oxidation, reduction, hydrolysis
Expose functional group
Phase II reactions
Synthetic
Conjugation
Use conjugating reagents
Transferase enzyme
What may phase II reactions activate?
- active, high energy form of conjugating agent
- drug may be activated to high energy compound that reacts with conjugating agent in presence of transferase enzyme
Drug elimination
Refers to the irreversible removal of drug from body by all routes of elimination
Drug excretion
Removal of the intact drug
Biotransformation or drug metabolism
Process by which the drug is chemically converted in the body to a metabolite
Kidney functions
- secretion of renin, regulates blood pressure
- secretion of erythropoietin, stimulates RBC production
Renal blood flow (RBF)
Volume of blood flowing through the renal vasculature per unit time
Exceeds 1.2 L/min
Renal plasma flow (RPF)
Renal blood flow minus volume of RBCs present
Glomerular filtration rate (GFR)
120 mL
Filtration fraction
GFR/RPF
RBF and GFR relationship
Remain relatively constant even with large difference in mean systemic blood pressure
What helps keep constant blood flow and filtration fraction fairly constant?
Autoregulation
What is filtered through the glomerulus from the plasma?
Only unbound small molecules
What type of drugs are eliminated by renal excretion
- nonvolatile
- water soluble
- low MW
- slowly transformed by liver
What processes may drugs be excreted by kidney?
Glomerular filtration
Active tubular secretion
Tubular reabsorptioin
For a weak acid drug, is the extent of dissociation more affected by changes in the urinary pH if the pKa is 5 or 3?
More affected if pKa if 5
PKa <2 are slightly affected
Drug clearance
Elimination from body without identifying mechanism of process
Considers the entire body as a single drug eliminating system from which many unidentified elimination processes may occur
