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Pharmacokinetics (PK)
The study of the disposition of a drug The disposition of a drug includes the
processes of ADME Absorption Distribution Metabolism Excretion Toxicity
Elimination
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)
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
A drug can be rapidly metabolized.
Routes Of Administration
Routes Of Drug Administration
EnteralParenteral
OralInjection RectalRespiratoryTopical
Absorption
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.
Most drugs undergo gastrointestinal absorption. This is extent to which drug is absorbed from gut lumen into portal circulation
Exception: IV drug administration
Absorption relies on Passage through membranes to reach the blood passive diffusion of lipid soluble species.
The Process
The Rule of Five - formulation
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.
Poor absorption or permeation are more likely when:
Absorption & Ionization
Non-ionised drug
More lipid soluble drug
Diffuse across cell membranes more
easily
First Pass Metabolism
Bioavailability: the fraction of the administered dose reaching the systemic circulation
Dose
Destroyed in gut
Notabsorbed
Destroyed by gut wall
Destroyedby liver
tosystemiccirculation
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 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.
Relationship Between Dose, Therapeutic Effect and Toxic Effect. The Therapeutic Index is Narrow for Most Cancer Drugs 100× 10×
DISTRIBUTION
Determined by: • partitioning across various membranes
•binding to tissue components
•binding to blood components (RBC, plasma protein)
•physiological volumes
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:
intravascular (blood plasma found within blood vessels) interstitial/tissue (fluid surrounding cells) intracellular (fluid within cells, i.e. cytosol)
The distribution of a drug into these compartments is dictated by it's physical and chemical properties
Distribution
Apparent volume of distribution (Vd) =
Amt of drug in body/plasma drug conc
VOLUME OF DISTRIBUTION FOR SOME DRUGS
DRUG Vd (L)cocaine 140
clonazepam 210amitriptyline 1050amiodarone ~5000
Factors affecting drugs Vd
Blood flow: rate varies widely as function of tissueMuscle = slowOrgans = fast
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
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.
Physiochemical properties-Po/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
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
Physiochemical Properties-Size 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
•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.
Elimination
The irreversible removal of the parent drugs from the body
Elimination
Drug Metabolism (Biotransformation)
Excretion
Drug Metabolism
The chemical modification of drugs with the overall goal of getting rid of the drug
Enzymes are typically involved in metabolism
Drug
MetabolismMore polar
(water soluble)Drug
Excretion
•From 1898 through to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. Bayer marketed heroin as a cure for morphine addiction•Heroin is converted to morphine when metabolized in the liver
METABOLISM
Phases of Drug Metabolism
Phase I Reactions
Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) eg. oxidation
Often these metabolites are inactive
May be sufficiently polar to be excreted readily
Phases of metabolism
Phase II Reactions
Conjugation with endogenous substrate to further increase aqueous solubility
Conjugation with glucoronide, sulfate, acetate, amino acid
The Most Important Enzymes
Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs
Act on structurally unrelated drugs
Metabolize the widest range of drugs.
• Found in liver, small intestine, lungs, kidneys, placenta
• Consists of > 50 isoforms
• Major source of catalytic activity for drug oxidation
• It’s been estimated that 90% or more of human drug oxidation can be attributed to 6 main enzymes:• CYP1A2 • CYP2D6• CYP2C9 • CYP2E1• CYP2C19 • CYP3A4
In different people and different populations, activity of CYP oxidases differs.
CYP family of enzymes
Inhibitors and inducers of microsomal enzymes
Inhibitors: cimetidine prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs)
Inducers: barbiturates, carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents
Blockers: acting on non-microsomal enzymes (MAOI, anticholinesterase drugs)
Phase II
Main function of phase I reactions is to prepare chemicals for phase II metabolism and subsequent excretion
Phase II is the true “detoxification” step in the metabolism process.
Phase II reactions
Conjugation reactions
Glucuronidation (on -OH, -COOH, -NH2, -SH groups)
Sulfation (on -NH2, -SO2NH2, -OH groups)
Acetylation (on -NH2, -SO2NH2, -OH groups)
Amino acid conjugation (on -COOH groups)
Glutathione conjugation (to epoxides or organic halides)
Fatty acid conjugation (on -OH groups)
Condensation reactions
Glucuronidation
Conjugation to a-d-glucuronic acid
Quantitatively the most important phase II pathway for drugs and endogenous compounds
Products are often excreted in the bile
Phase I and II - Summary
Products are generally more water soluble
These reactions products are ready for (renal) excretion
There are many complementary, sequential and competing pathways
Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathways
Excretion
The main process that body eliminates "unwanted" substances.
Most common route - biliary or renal
Other routes - lung (through exhalation), skin (through perspiration) etc.
Lipophilic drugs may require several metabolism steps before they are excreted