Pharmacokinetics 课件

Why drugs fail
Importance of PK studies
Patients may suffer:
Toxic drugs may accumulate
Useful drugs may have no benefit because doses are too small to establish therapy
DISTRIBUTION
All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments:
Plasma Protein Binding
Many drugs bind to plasma proteins in the blood steam
Plasma protein binding limits distribution.
A drug that binds plasma protein diffuses less efficiently, than a drug that doesn’t.
A drug can be rapidly metabolized.
Routes Of Administration
Routes Of Drug Administration
Parenteral
Enterry
Rectal
Oral
Absorption
absorbed by gut wall by liver
Dose
to systemic circulation
Bioavailability: the fraction of the administered dose reaching the systemic circulation
Determination of bioavailability
A drug given by the intravenous route will have an absolute bioavailability of 1 (F=1 or 100% bioavavailable)
While drugs given by other routes usually have an absolute bioavailability of less than one.
The Rule of Five - formulation
Poor absorption or permeation are more likely when:
There are more than 5 H-bond donors. The molecular weight is over 500. The LogP is over 5. There are more than 10 H-bond acceptors.
The process by which drug proceeds from the site of administration to the site of measurement (blood stream) within the body.
Necessary for the production of a therapeutic effect.
DRUG Vd (L) cocaine 140 clonazepam 210 amitriptyline 1050 amiodarone ~5000
Factors affecting drugs Vd
Blood flow: rate varies widely as function of tissue Muscle = slow Organs = fast
PHARMACOKINETICS
“What the body does to the drug”
Pharmacokinetics (PK)
The study of the disposition of a drug
The disposition of a drug includes the processes of ADME
DISTRIBUTION
Determined by: • partitioning across various membranes •binding to tissue components •binding to blood components (RBC, plasma protein) •physiological volumes
•Antibodies and other drugs range into the thousands of daltons •Drugs >200 Da with low Po/w values cannot passively cross membranes- require specialized protein-based transmembrane transport systems- slower distribution •Drugs < thousand daltons with high Po/w values-simply diffuse between the lipid molecules that make up membranes, while anything larger requires specialized transport.
Absorption & Ionization
Non-ionised drug
More lipid soluble drug Diffuse across cell
membranes more easily
First Pass Metabolism
Destroyed in gut
Not
Destroyed Destroyed
Physiochemical PropertiesSize of drug
•The size of a drug also dictates where it can go in the body. •Most drugs : 250 and 450 Da MW •Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through cell membranes
Most drugs undergo gastrointestinal absorption. This is extent to which drug is absorbed from gut lumen into portal circulation
Exception: IV drug administration
The absolute bioavailability is the area under curve (AUC) non-intravenous divided by AUC intravenous
.
Toxicity
The therapeutic index is the degree of separation between toxic and therapeutic doses.
Capillary structure: •Most capillaries are “leaky” and do not impede diffusion of drugs •Blood-brain barrier formed by high level of tight junctions between cells •BBB is impermeable to most water-soluble drugs
Blood Brain Barrier
•Disruption by osmotic means •Use of endogenous transport systems •Blocking of active efflux transporters • Intracerebral implantation •Etc
Relationship Between
Dose, Therapeutic Effect
and Toxic Effect. The
Therapeutic Index is
Narrow for Most Cancer
Drugs
100×
10×
Distribution
The movement of drug from the blood to and from the tissues
Drugs with low Po/w values (meaning that they are fairly water-soluble) are often unable to cross and require more time to distribute throughout the rest of the body
intravascular (blood plasma found within blood vessels) interstitial/tissue (fluid surrounding cells) intracellular (fluid within cells, i.e. cytosol)
I.V Drug
IV vs Oral
Oral Drug
Immediately Delayed
completely
incomplete
The Process
Absorption relies on Passage through membranes to reach the blood passive diffusion of lipid soluble species.
Physiochemical propertiesPo/w
The Partition coefficient (Po/w) and can be used to determine where a drug likes to go in the body
Any drug with a Po/w greater than 1(diffuse through cell membranes easily) is likely be found throughout all three fluid compartments
The distribution of a drug into these compartments is dictated by it's physical and chemical properties
TOTAL BODY WATER
Vascular
Extravascular
Intracellular
3L
9L
28 L
4% BW
13% BW
41% BW
Distribution
Apparent volume of distribution (Vd) =
Amt of drug in body/plasma drug conc
VOLUME OF DISTRIBUTION FOR SOME DRUGS
Absorption
Distribution
Metabolism Excretion
Elimination
Toxicity
ADMET
DRUG R&D
Drug discovery and development •10-15 years to develop a new medicine •Likelihood of success: 10% •Cost $800 million – 1 billion dollars (US)