ADME Flashcards
A scientific discipline that aims to quantitatively characterize the effect of the body on the drug
Pharmacokinetics (PK)
ADME
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 another
Excretion: Removal of the drug product (or metabolite) from the body
The drug to travel form its site of administration to its target site at desirable concentrations and at desirable time frame
The overall goal in drug therapy
The site of action is localized around the site of administration
Local drug administration
The site of action is far from the site of administration and must be transported via the bloodstream
Systemic drug administration
A common route of drug administration
Extravascular route
Before the drug is absorbed through the GI walls,
It should be available as molecules solubilized in the interstitial fluids
Solid must under go ______ and liquid must under go _____
Solids must undergo disintegration and dissolution, liquids much undergo dissolution
For most drugs, the optimum site for drug absorption after oral administration is
The upper portion of the small intestine or duodenum region
The anatomy of the duodenum provide:
- large surface area for the drug to passively diffuse
- high perfusion through a large network of capillaries
Large particles are delayed for ______ by the presence of food in the stomach
3-6 hours
Gastric emptying of solids v. Liquids
About 50% of liquids empty in 20 minutes
About 50% of solids remain after 2 hours
Small intestine pH gradient and what it means
(6.5-7)
Retention time is about 3-4 hours
Independent of solid particle size or fed status
Gradient bacterial content duodenum (sterile) to ileum (confluent)
Large intestine pH and what it means
(7)
Avg, takes 53 hours from ingestion to excretion
Unabsorbed molecules spend ~90% of time in large intestine and rectum (minimum absorption)
Highest bacterial content (anaerobic)
The 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
Bioavailability
Fraction of the administered dose which reaches the systemic circulation relative to an intravenous dose (F)
Absolute bioavailability
Bioavailability data are used to determine:
- amount of drug absorbed from dosage form
- rate at which the drug was absorbed
- duration of the drug’s presence in the biologic fluid or tissue
- relationship between drug blood levels and clinical efficacy and toxicity
FDA requires bioavailability data for
NDA, Abbreviated NDA, supplemental applications (for changes in manufacturing, new indications, and new/additional doses)
The rates of absorption and elimination are equal
Peak height concentration (Cmax)
MEC
Minimum effective concentration, must be achieved for the patient to exhibit adequate response
MTC
Minimum toxic concentration
Relationship between dose and Cmax
Cmax (and AUC) increase with increased dose
Reflects the rate of absorption from a formulation, which determines the time needed for the MEC to be reached and to maintain it
Time of Peak (Tmax)
Changes in the rate of drug absorption change the
Cmax and Tmax
When the rate of abortion is decreased
Cmax is lowered and Tmax occurs at a later time
The serum blood concentration over time; measure of the total amount of drug absorbed into the circulation following the administration of a single dose
AUC (area under curve)
If equivalent doses of a drug in different formulations provide different AUC values =
Differences in the extent of absorption (Graph on Slide 23)
—-Formulation A Delivers much greater amt of drug to circulatory system than other two formulations
Oral dosage strengths are based on considerations of the proportion of the dose
That is expected to be aborbed
The absolute bioavailability following oral dosing is compared to
IV dosing
When F is less than 1, oral doses
Must be larger than IV doses to provide the same concentration of drug in the plasma
As bioavailability worsens,
The variability from patient to patient tends to increase
What enzyme in the liver is responsible for a lot of drug metabolism?
Cytochrome C
What does this equation and the components mean?
F = Fa X Fi X Fh
F= bioavailability Fa= the fraction of the administered dose that is not destroyed in the gut or lost in feces Fi= the fraction of the dose that escapes metabolism in the intestinal wall Fh= the fraction of the dose that escapes metabolism on first-pass through the liver
Transport without external energy and molecules diffuse randomly in all directions
Passive Transport
The rate of transfer of diffusion
Flux (measured in mass per unit area)
Molecules diffuse from a region of high concentration to a region of low concentration
Fick’s law of diffusion
The location, extent, and degree of distribution are dependent on
The drug’s properties and individual patient characteristics
Drugs can distribute into these fluids
- Plasma (3 L)
- Intracellular water (27 L)
- Interstitial water (12 L)
Where the drug dissolves affects concentration
Drugs are present in the body in two states
Bound (to protein)
Free (plasma, interstitial fluid and lymph, tissues)
What drugs diffuse across the membrane the easiest?
Hydrophobic, small, not bound to plasma protein
The pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue
Hydrostatic pressure
The difference between the capillary hydrostatic pressure and the blood osmotic pressure
Net Filtration pressure (NFP)
As the blood newly enters the capillary (arterial end) the pressure of the capillary blood is slightly higher than that of tissue causing
Fluid to leave the capillary bed and enter the tissues
Also known as: hydrostatic or filtration pressure
Venues have lower pressure than tissue fluids allowing the filtered fluid to
Return to the venous capillary
Also known as absorptive pressure
Partitioning and accumulation of a drug in the tissue or organ
Drug affinity
The time for the drug distribution is generally measured by the time for 50% distribution
Distribution half life
Relation to the blood flow to the organ, the volume of the organ, and the partitioning of the drug into the organ tissues
Distribution Constant
An estimated value used because the true volume a drug is absorbed into (distributed) is not known
Volume of Distribution
It is not a physiological volume, it is hypothetical
Determined by the same physiological and drug-related factors that control drug distribution
Volume of Drug distribution
The decline from peak plasma concentrations after drug administration results from drug elimination or removal by the body
Metabolism
Elimination of most drugs from the body involves both
Metabolism (bio transformation) and renal excretion
The principle site of metabolism is
The liver
The enzymes responsible for oxidation and reduction of drugs and certain metabolites are monoxygenase enzymes know as
Mixed-Function Oxidases
Constitute ETC enzymes
The terminal component of the electron transport chain in the ER and acts as both an oxygen and substrate binding locus for drugs and endogenous substrates
Cytochrome P-450
Responsible for metabolism >70% of drugs
Cytochrome-P450
Families (numbers) and subfamilies (letters)
CYP2c(, 2C19, and 3A4 >50% of oral drugs
Inactive and must be biotransformed in the body to metabolites that have pharmacological activity, intentionally designed to improve drug stability, increase systemic absorption, or prolong activity
Pro drugs
What are the two major groups of reactions for pathways of drug biotransformation
Phase I (asymmetric): oxidation, reduction, hydrolysis Phase II (synthetic): conjugation
Phase I biotransformation reactions usually occur
First and introduce or expose a functional group on the drug molecule
Once a polar constituent is recreated or placed into the molecule
A phase II reaction may occur
Derived from biochemical compounds involved in carbohydrate, fate, and protein metabolism
Conjugating reagents
Refers to the irreversible removal of drug from the body by all routes of elmination
Drug elimination
Drug elimination is usually divided into two components
Excretion and Biotransformation
The removal of the intact drug
Drug excretion
The process by which the drug is chemically converted in the body to a metabolite
Biotransformation or drug metabolism
The main excretory organ for the removal of metabolic waste products and plays a major role in maintaining the normal fluid volume and electrolyte composition
Kidney
To maintain salt and water balance, the kidney
Excretes excess electrolytes, water, and waste products while conserving solutes necessary for proper body function
The two endocrine functions of the kidneys
- Secretion of renin to regulate BP
2. Secretion of erythropoietin, which stimulates RBC
Briefly describe the anatomy of renal filtration
- Kidney is supplied blood via the renal artery
- Each arterial carries blood into nephrons to Bowman’s capsule to filter the blood in the glomerulus
- Blood flows out into a second capillary network that surrounds the tubules including the Loop of Henle
The volume of blood flowing through the renal vasculature per unit time
Renal Blood Flow (RBF) 1.2 L/min or 1700 L/d
The renal blood flow minus the volume of RBCs present, important factor in the rate of drug filtration at the glomerulus
Renal plasma flow (RPF)
About 120 mL/min or 180L/d
Glomerular filtration rate (GFR) about 20% of the RPF
Ratio of GFR/RPF
Filtration fraction
The process by which a drug is excreted via the kidneys may include
Glomerular filtration, active tubular secretion, and tubular reabsorption
The ratio of the sum of the glomerular filtration and active secretion rates less the reabsorption rate divided by the plasma drug concentration
Renal clearance
May give an indication for the mechanism of renal excretion of the drug
Clearance ratio
<1 — drug is partially reabsorbed
=1 — drug is filtered only
>1 — drug is actively secreted
