Introduction and Overview

Pharmacokinetics

The study of kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs and their corresponding pharmacological, therapeutic, and toxic responses in humans and animals

Applications

Bioavailability measurements

Effects of physiological and pathological conditions on drug disposition and absorption

Dosage adjustment of drugs in disease states, if and when necessary

Correlation of pharmacological responses with administered doses

Evaluation of drug interactions

Clinical prediction

Using pharmacokinetic parameters to individualize the drug dosing regimen and thus provide he most effective drug therapy

Biopharmaceutics

The study of the factors that influence the bioavailability of a drug in humans and animals and the use of this information to optimize pharmacological and therapeutic activity of drug products

Factors

Chemical nature of a drug

Weak base

Weak acid

Inert excipients used in the formulation of a dosage form

Diluents

Binding agents

Disintegrating agents

Coloring agents

Others!

Method of manufacture

Dry granulation

Wet granulation

Physicochemical properties of drugs

pKa

Particle size

Size of distribution

Partition coefficient

Polymorphism

Others!

Relationship between the administered dose and the amount of drug in the body

Intravenous solution

The amount of drug that reaches general circulation is the dose administered

Dose = X₀ = (AUC)₀∞ * KV

(AUC)₀∞ = area under curve of plasma drug concentration versus time (AUC) from time zero to time infinity

K = first-order elimination rate constant

V = (or Vd) drug's volume of distribution

The apparent volume into which a given mass of drug would need to be diluted in order to give the observed concentration

Extravascular route

The amount of drug that reaches general circulation is the product of the bioavailability fraction (F) and the dose administered

F * Dose = FX₀ = (AUC)₀∞ * KV

Onset of action

The time at which the administered drug reaches the therapetuic range and begins to produce the effect

Duration of action

The time span from the beginning of the onset of action to the termination of action

Termination of action

The time at which the drug concentration in the plasma falls below the minimum effective conentration (MEC)

Therapeutic range

The plasma or serum concentration range within which the drug is likely to produce the therapeutic activity or effect

Amount of drug in the urine

Used to obtain selected pharmacokinetic parameters of a drug as well as other useful information such as bioavailability

Absorption

The process by which a drug proceeds from the site of administration to the site of measurement

Distribution

The process of reversible transfer of drug to and from the site of measurement (usually blood or plasma)

Any drug that leaves the site of measurement and does not return has undergone elimination

Rate and extent of drug distribution is determined by

Factors

The binding of a drug to plasma proteins and tissue components

How well the tissues and/or organs are perfused with blood

The permeability of tissue membranes to the drug molecule

Controlled and determined by the physicochemical properties and chemical structures of a drug molecule

Metabolism

The process of conversion of one chemical species to another chemical species

Usually, metabolites posses little or none of the activity of the parent drug (there are exceptions)

Elimination

The irreversible loss of drug from the site of measurement

Methods

Metabolism

Excretion

The irreversible loss of a drug in a chemically unchanged or unaltered form

Principal organs

Liver

Primary organ where drug metabolism occurs

Kidney

Primary site for removal of a drug in a chemically unaltered or unchanged form (i.e. excretion) as well as for metabolites

Other organs

Lungs

Occasionally may be important for the elimination of substances with a high vapor pressure (e.g. gaseous anesthetics, alcohol, etc.)

Mother's milk (for infants)

Not a significant route of elimination for mother

Drug may be consumed in sufficient quantity to affect the infant

Disposition

Once a drug is in systemic circulation, it is distributed simultaneously to all tissues including the organ responsible for its elimination

The components of disposition

Distinction between elimination and distribution

When the distinction is undesirable or unclear, disposition is the term used

Defined as all processes that occur subsequent to the absorption of the drug

Intravascular route

Important features of the intravascular route of drug administration

There is no absorption phase

There is immediate onset of action

The entire administered dose is available to produce pharmacologic effects

The route is used more often in life-threatening situations

Adverse reactions are difficult to reverse or control

Accuracy in calculations and administration of drug dose is critical

Routes

Intra-arterial

Intravenous

Extravascular route

Routes

Transdermal

Sublingual or buccal

Oral

Intramuscular

Subcutaneous

Rectal

Inhalation

Imporant features of extravascular routes of drug administration

An absorption phase is present

The onset of action is determined by factors such as formulation and type of dosage form, route of administration, physicochemical properties of drug, and other physiological variables

The entire administered dose of a drug may not always reach general circulation (i.e. incomplete absorption)

Linear pharmacokinetics

There is a directly proportional relationship between the observed plasma concentration and the amount of drug eliminated in the urine and the administered dose of the drug

Drug transfer in the body is possibly mediated by passive diffusion

Compartment model

Facts and definition

The most useful model in pharmacokinetics

The complexity of ADME makes it necessary to sometimes assume a simplified model

The body is conceived to be composed of mathematically interconnected compartments

Use and selection

Used in pharmacokinetics when it is necessary to describe the plasma concentration versus time data adequately and accurately

Allows accurate estimates of selected fundamental pharmacokinetics parameters like the apparent volume of drug distribution, the elimination half life, and the elimination rate constant of a drug

Provides the desired plasma concentration and duration of action for an administered drug

The selection of a compartment model depends solely upon the distribution characteristics of a drug following its administration

The terms rapid and slow distribution refer to the time required to attain distribution equilibrium for the drug in the body

Rapid distribution

If a drug is rapidly distributed following its administration, a one-compartment model will do an adequate job of accurately and adequately characterizing the plasma concentration versus time data

Suggests the rate of transfer between blood and tissues reaches equilibrium instantaneously after administration

All organs and tissues are behaving similarly towards the drug

Slow distribution

Generally, the slower the drug distribution characteristics of a drug, regardless of the route of administration, the greater the number of compartments required to characterize the plasma concentration versus time data and the more complex the nature of the equation employed

Suggests the distribution equilibrium is attained slowly and at a finite time (from several minutes to a few hours, depending on drug)

Suggests that the vasculature, tissues, and organs are not behaving the same way towards the drug

The body must be considered as two or more compartments

Compartments

Highly perfused systems like the liver and kidneys may be pooled together with the blood in one compartment

The tissues that are not highly perfused like the bones, cartilage, fatty tissue, and many others can be pooled together as one compartment

In this type of model, the rate of drug transfer from compartment 1 to 2 and vice versa becomes equal at at time greater than zero (from several minutes to hours)

Distribution equilibrium

When distribution equilibrium is attained, the rate of transfer between the blood and tissue and vice versa is equal

Depends on availability of plasma concentration versus time data

Factors

How often plasma samples are taken

How sensitive the analysis of concentration in plasma is

Physicochemical properties of a drug

Types

One compartment

Intravenous bolus

The straight line indicates there's only one pharmacokinetic phase, in this case, elimination

IV administration means there's no absorption phase

The straight line also suggests distribution is instantaneous

Cp = (Cp)₀ * e ^ -Kt

Cp = plasma concentration at any time, t

(Cp)₀ = plasma concentration at time = 0

One compartment is appropriate because there is a single phase in the concentration versus time plot and one exponential term in the equation

Extravascular

Two compartment

Intravenous bolus

Two phases, alpha (α) and beta (β)

Alpha phase is the first part of the curve (curvilinear) and is where the drug is being distributed in the body

Beta phase is after some time when the line becomes straight and distribution equilibrium has been reached

Cp = A * e ^ -αt + B * e ^ -βt

Since there's two phases, a two exponent equation is needed

Terms

A & Alpha (α) = associated with drug distribution

B & Beta (β) = associated with drug after distribution

Since there's a two exponent equation and two phases, a two component model is needed

Extravascular

Three phases

Absorption phase

Alpha (α) distribution phase

Beta (β) post-distribution phase

Since there are three phases, a two compartment model with

Three or more compartments

The type of model and route of administration influence which equation is used to characterize plasma concentration versus time data