Pharmacokinetics 1:

Introduction
Book Chapter 1

Lecture Outline ADME and ADME processes Routes of Administration Amounts in Plasma Pharmacokinetic Models Rate Processes and Constants

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Pharmacolkinetics: Definition
What is Pharmacokinetics?

A quantitative approach to the fate of drugs in the body

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Pharmacolkinetics: Definition
Even if a drug has the best efficacy at its receptor, it will only work well if it reaches its target (the place where it should act) with the right concentration and with the right timing and duration Pharmacokinetics deals with concentration of a drug in a central compartment (blood, plasma) after administration of a drug dose(s). The aim to characterize the kinetic processes (= rate processes) of an administered dose(s) of drugs
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ADME and ADME Processes

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Pharmacolkinetics: ADME
Pharmacokinetics deals with the drugs ADME: - Absorption )( - Distribution )( - Metabolism - Excretion )(

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Pharmacolkinetics: ADME
Absorption: is the process by which the drug proceeds from the site of administration to the site of measurement (usually plasma, serum or blood) Distribution: the reversible transfer of the drug from the site of measurement (to muscle tissue, fat etc.) Metabolism: the chemical conversion to other (mostly inactive) molecules Excretion: the irreversible loss of drug from the body in the unchanged form
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Pharmacolkinetics: ADME
Two other important terms are related to ADME: Elimination )(: irreversible loss of drug from the site of measurement due to metabolism + excretion Disposition )(: the processes of distribution and elimination overlap can not always be separated. Disposition is loss of drug from the site of action due to distribution + elimination

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Pharmacolkinetics: ADME

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Routes of Administration

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Routes of Administration )=(

There are two main types of route of administration: - Intravascular (into the blood vessels) - Extra-vascular (all other types) These two types are fundamentally different in their pharmacokinetic properties and therefore, are treated separately in PK

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Intra- Vascular Administration

Intra-arterial )-( Intrevenous )-( The features of IV administration are: 1. There is no absorption phase 2. The entire dose available (F=100%) 3. There is an immediate onset of action 4. Adverse effect are hard to control dose must be exact Because of these features, IV administration is used mostly in life-threatening situations Two types:
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Extra- Vascular Routes

The main types: Oral administration (per os, P.O. ( Intamuscular a.(i.m. ) Subcutaneous a.(s.c. -) Buccal or sub-lingual a. (absorption through buccal membrane) Rectal a. )( Transdermal a. (patch) Inhalation (gas or inhaler)
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Extra- Vascular Routes

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Amounts in Plasma

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Amount in the Body

Normally, only a fraction of the administered ) (dose reaches the circulation, and a fraction of that actually causes the therapeutic effect For intravenous administration, nearly 100% reaches the circulation: Dose = X0 = (AUC) 0 KVd Where: K is the first order elimination constant V or Vd is the apparent volume of distribution
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Amount in the Body

For extravascular administration, X0 (AUC) 0 KVd but: FDose = FX0 = (AUC) 0 KVd Where: F is the bioavailability the fraction (in%) of drug that reaches the circulation and is available to exert the therapeutic effect So, in order to characterize the pharmacokinetics of a drug, we need to know at least its elimination constant, distribution volume and bioavailability
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Plasma Concentration-in-Time Curves

A typical curve for extravascular administration looks like this (for single dosing):

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Plasma Concentration in Time Curves

In the graph we see that if we know: - the minimal effective concentration (MEC), - and the minimal toxic concentration (MTC), we can determine the onset of action, the termination of action, and the duration of action Notice the drug plasma concentrations are in mass/vol
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Pharmacokinetic Models

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Linear Pharmacokinetics
Most ADME processes have equation containing the term ex or e-x So ADME processes are typically first order processes This suggests that they occur mostly by passive diffusion Therefore, the processes (e.g. elimination) are directly proportional to the dose administered If this proportionality exists we say that the pharmacokinetics (PK) is linear
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Compartments Concept
Because ADME processes are very complex, we must simplify This is done by assuming ) (a compartment model The body is described as 1, 2, 3 or more compartments )( More compartments more complex models

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Compartments Concept
Usually, blood and well-perfused organs (lungs, kidneys, liver) are pooled in one compartment com. 1 = central compartment Other parts: fat tissue, bone, cartilage are comp. 2 peripheral tissue compartment Choice of model depends on the drug distribution Fast (immediate) equilibrium between central and other compartments one compartment model Equilibrium at time significantly >0 two compartment model
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1 Compartment: Bolus IV Administration

Intravascular bolus injection is the most basic model A one compt. model has the general equation:

Cp= (Cp)0 e-kt

concentration at time t and (Cp)0 at t=0
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Where Cp is the plasma

2 Compartments: Bolus IV Administration

In a two compt. model has the general equation:

Cp= Ae-t + Be-t

Where A and are the parameters associated with the distribution phase and B and are those associated with the post-distribution
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1 Compartment: Extravascular Ad.

Because there are two phases: absorption and elimination we also need a bi-exponential equation
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1 Compartment: Extravascular Ad.

The general equation is:

Where:

(Xa)t=0 is the amount of drug that can be absorbed (absorbable amount) Ka is the first order absorption rate const. K is the first order elimination rate const. X0 is administered dose, F is the absorbable fraction V is the distribution volume
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2 Compartment: Extravascular Ad.

There are 3 phases Therefore, we would need a tri-exponential equation We will not deal with 2-compartment models equations only describe their general features

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How Model Are Used

Compartments are not measured (too impractical) and not defined in PK We always use the simplest model that can describe the experimental data If the a simple model doesnt fit, we try a higher order When a model fits, it can be used for predictions, calculation of dose, administration regimen and adjustment of dose to individuals One and two compartment models are used, three compt. order are not
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Measurable Quantities
We can not measure absorption, distribution and metabolism directly We can measure the blood levels in time and the excretion in urine (and feces) of the parent (unchanged) drug and its metabolites Mass balance considerations dictate that at time t - For intravascular route: Dose = amount in body + amount metabolized + cumulative amount excreted (unchanged)
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Time Curve of Masses

- For extravascular administration: F(Dose) = absorbable amount at absorption site + amount metabolized + cumulative amount excreted

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Time Curve of Masses

- The figure below shows the passage of masses: Absorption site Body Out of body - Each of the steps has a rate constant )(

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Rate Processes and Constants

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Rate processes and Process Order

The change in the concentration in each
compartment, Y is:

The general equation is: dY/dt = KYn

where n is the order of the process There are: zero order, first order, second order third order, reversible, parallel and consecutive processes In PK, we usually deal with zero and first order processes
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The Zero Order Process

In a zero order process:
-dY/dt = K0Y0 = K0
This means a constant rate process, independent of of Y (amount of enzyme, transporter etc.) Integration yields:

Y = Y0 - K0t
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The Zero Order Process Graph

In a zero order process:

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Application of the Zero Order Process

Application of the zero order process include: - Intravenous (IV) infusion - Controlled release formulations - Transdermal (patch) administration In all these, the rate of input is constant The units of the zero order rate constant K0 are: mass/time, for eliminations mostly mg/hour

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The First Order Process

In a first order process: dY/dt = KY1 = KY
Integration yields: Y = Y0 e-kt
lnY = lnY0- Kt logY= lnY0- Kt/2.203

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The First Order Process

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Application of First Order Process

First order processes are the most common and most widely used in PK modeling Intravenous bolus and almost all elimination processes can be modeled with first order equations

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First Order Constant - units

The rate constant of first order processes has different units. Zero order: -dY/dt = K0Y0 = K0 , K in mass/time
First order process: -dY/dt = KY K = -dY/Ydt in mass/masstime time-1

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Zero vs. First Order Data

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