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 Absorption Distribution Metabolism Excretion Toxicity

Elimination

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)

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

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

IV vs Oral

I.V Drug Oral Drug

Immediately Delayed

completely incomplete

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 & IonizationNon-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 The movement of drug from the blood

to and from the tissues

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

TOTAL BODY WATERVascular

3 L

4% BW

Extravascular

9 L

13% BW

Intracellular

28 L

41% BW

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 bodyElimination

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

DrugMetabolism More 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

Mostly occurs in the liver because all of the blood in the body passes through the liver

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

ADME - Summary