Pharmacokinetics

All processes from the site of administration to the site of measurement

Placement of drug molecule directly into the blood stream (i.v.)

Oral, sublingual, subcutaneous, rectal, intramuscular administration

The fraction of an extravascularly administered drug which reaches the circulation intact. Represented by F

(measure of the extent of absorption of unchanged drug)

Assessed with reference to an i.v. dose

Comparison of the bioavailability between formulations of a drug given either by the same or different routes of administration

Formulations containing the same dose of the same chemical entity, generally in the same dosage form, intending to be interchangeable

Have to be within limits (usually +/- 20% around reference product - not necessarily exactly the same

Disintegration time

Dissolution rate

Movement through membranes (perfusion or permeability limitations)

Gastric emptying

Intestinal transit

First pass metabolism in gut/liver

Transcellular

Paracellular

Efflux transporters

Through the cell

Passive diffusion, active transport or facilitated transport

- dependent on conc gradient

- transport continues until equilibrium is reached

Dependent on;

- Lipophilicity

- Molecular size

- Degree of ionisation

- Molecular structure (H-donor/acceptor, functional groups)

- Surface area available (varies along gut)

Between the cells

Passive diffusion

- Important for polar, hydrophilic molecules

- Dependent on molecular size, size and density of junctions, surface area

e.g. P-glycoprotein

Can reduce oral absorption as a result of efflux in the intestinal lumen

Membrane offers no effective barrier to drug

Molecule readily passes across membrane

- small, lipophilic molecules

- very small hydrophilic molecules

Absorption rate varies with blood flow

Molecule has difficulty passing through membrane

Absorption insensitive to changes in blood flow

Large, polar hydrophilic molecules

e.g. gentamycin, streptomycin, vancomycin, cefotaxamine, pyridostigmine

Barrier different to gut wall

Major difference in paracellular route - pores larger - more readily absorbed compared to oral

Generally perfusion rate limited irrespective of polarity and pka of compound

2 options

Release/dissolution rate limited (more common)

Permeability rate limited absorption

Permeability changes along GIT affect changes in rate limitation

Important for sustained release formulations

Poorly permeable drugs not good candidates for extended release formulations

Surface area

Blood flow

Permeability

All greater for small intestine compared to the stomach

All drugs in solution are absorbed faster in small intestine, even acids

Metoclopramide - increases gastric emptying

Anticholinergic - reduces gastric emptying

Only rate is affected, not extent

Fasted - fast delivery to upper small intestine, no major difference between particle sizes

Fed - delayed gastric emptying, affects rate of absorption, difference between particle sizes

Small intestine - food has no effect on transit time in the small intestine, no difference between different particle sizes

Lack of time (esp oral route) - due to;

- low intestinal permeability with large polar molecule (e.g. neomycin)

- poor dissolution (solubility)


Competing reaction

- enzymatic (intestinal P450, interplay with efflux transporters)

- non-enzymatic (complexation)

Intestinal and hepatic extraction

- for orally administered drugs

Amitriptyline

Diltiazem

5-fluorouracil

Labetolol

Lidocaine

Mercaptopurine

Morphine

Neostigmine

Nifedipine

Propranolol

Verapamil

Delivery of drug to tissue by perfusion

Tissue membrane permeability

Binding of drug to plasma and tissue components and partitioning into fat

Occurs when the membrane separating the blood from the tissues is not a barrier to drug distribution

Likely to occur with small and lipophilic molecules distributing across thin membranes

Likely to occur with polar molecules and relatively impermeable membranes

Muscle, kidney - capillary porous, barrier at cellular level

CNS - barrier at capillary level

Apparent volume that a drug occupies at a concentration equal to that in the plasma

Hypothetical - rarely a physiological space (e.g. total body water)

Can vary from 7-50000L+/70kg

Relates measured plasma drug conc (C) to the amount of drug in the body (A)

V= A/C

Reference fluid measured (plasma, blood, unbound drug)

How the body handles the drug

What the drug does to the body

Reversible transfer of substance between site of measurement and other sites within the body

Irreversible loss of unchanged substance by chemical conversion

Irreversible loss of unchanged substance

Irreversible loss of unchanged substance from site of measurement

Elimination and distribution

Low oral bioavailability caused by loss of drug as it passes through eliminating organs/tissues (intestinal wall/liver) for the first time before entering the systemic circulation

Relates patterns of response (efficacy, toxicity) to drug administration following acute and chronic dosing

Helps provide a rational basis for drug design, selection and dose regimen design

Helps quantitatively evaluate drug product performance in vivo and establish appropriate in vitro dissolution specifications

Provides a means for comparing data from different animal species

The time period which the drug in all the tissues comes into distribution equilibrium with the drug in the plasma

This occurs sooner with highly perfused tissues

Usually completes within 30 min to 5 hours - elimination during this phase is usually small

The time period when decline in concentration (C) reflects proportional loss from the body

It is characterised by t1/2 and V (vol of dist)

The apparent dilution space into which the drug distributes

The time taken for the plasma concentration (as well as amount in the body) to fall by one half, once distribution elimination has been achieved