Unit-3 Biopharmaceutics Basic Considerations

The term “Pharmacokinetics” is derived from Greek words Pharmakon- Drug & Kinesis-movement.
It is the quantitative study of drug movement in, through and out of the body and their relationship
with the pharmacological, therapeutic or toxicological response in man or animals.

The frequency of administration of a drug in a particular dose is called Dose regimen.

Several relevant terms can now be defined

➢ Clinical Pharmacokinetics is defined as the application of Pharmacokinetic principles in the

safe and effective management of individual patient.
➢ Population Pharmacokinetics is defined as the study of Pharmacokinetic differences of drugs
in various population groups.
➢ Toxicokinetics is defined as the application of pharmacokinetic principles to the design,
conduct and interpretation of drug safety evaluation studies.

Plasma Drug Concentration -Time Profile

A typical plasma concentration-time profile showing pharmacokinetic and pharmacodynamic

parameters, obtained after oral administration of single dose of a drug.

1).Pharmacokinetics Parameter (Mainly Three)

Peak Plasma Concentration (Cmax)

➢ It is the maximum drug concentration in plasma.

➢ Expressed in mcg/ml.
➢ At Cmax absorption rate = elimination rate.
➢ Peak concentration of any drug is related to its pharmacological response.

Time of Peak Concentration (tmax):

➢ Time taken by the drug to reach the maximum plasma concentration.

➢ Expressed in hours.
➢ Useful in estimating rate of absorption.
➢ Importance in assessing the efficacy of drugs used to treat acute conditions like pain and
insomnia.
Area Under the Curve (AUC):

➢ It represent the total integrated area under the plasma level-time profile and expresses the
total amount of drug that comes into the systemic circulation after its administration.
➢ Expressed in mcg/ml X hours.
➢ Important parameter in evaluating bioavailability of a drug from its dosage form.

2). Pharmacodynamics Parameter

Minimum Effective Concentration (MEC):

➢ It is defined as minimum concentration of drug in plasma required to produce therapeutic

effect.
➢ Concentration of drug below MEC is said to be in the sub-therapeutic level.
➢ In case of antibiotics, the term minimum inhibitory concentration (MIC) is used.

Maximum Safe Concentration (MSC):

➢ Concentration of drug in plasma above which adverse or unwanted effects are precipitated.
➢ Also know as minimum toxic concentration (MTC).
➢ Concentration of drug above MSC is said to be in toxic level.

Onset of Action:

➢ Beginning of pharmacological response.

➢ Occurs as the plasma drug concentration just exceeds required MEC.

Intensity of Action:

➢ Maximum pharmacological response produces by the peak plasma concentration of drug.

➢ Intensity of action depends on the height of peak plasma concentration.

Therapeutic range: (GPAT-20)

➢ Concentration of drug between MEC and MSC represent therapeutic range. Also know as
therapeutic window.

Therapeutic Index:

➢ Ratio of MSC to MEC.

➢ Also defined as the ratio of dose required to produce toxic or lethal effects to dose required to
produce therapeutic effect.

Pharmacokinetics Models
A model is a mathematic description of a biologic system and is used to express quantitative
relationships.

A compartment is a group of tissues with similar blood flow and drug affinity.

Pharmacokinetic models are hypothetical structures used to describe the rate of a drug in a
biological system following its administration.
Pharmacokinetic models are useful in-

1. Characterizing the behaviour of drugs in patients.

2. Predicting the concentration of drug in various body fluids with any dosage regimen.
3. Predicting the multiple-dose concentration curves from single dose experiments.
4. Calculating the optimum dosage regimen for individual patients.
5. Evaluating the risk of toxicity with certain dosage regimens.
6. Correlating plasma drug concentration with pharmacological response.
7. Evaluating the bioequivalence/bioinequivalence between different formulations of the same
drug.
8. Estimating the possibility of drug and/or metabolite(s) accumu-lation in the body.
9. Determining the influence of altered physiology/disease state on drug ADME.
10. Explaining drug interactions.

COMPARTMENT MODELS
A compartment is not a real physiological or anatomic region but an imaginary or hypothetical one
consisting of tissue/group of tissues with similar blood flow & affinity.

Our body is considered as composed of several compartments connected reversibly with each
other.

Depending on whether the compartments are arranged in parallel or in series Compartment models
are of two types

1) Mammilary Model
2) Catenary Model

1).Mammilary Model

Arrangement of compartments in a manner similar to connection of satellites to a planet (i.e joined

in parallel to central compartment)

Central compartment (compartment 1) Plasma, Highly perfused tissues (such as lung, liver kidney).

Peripheral compartment or tissue compartment (denoted by no. 2,3) low vascular & poor perfusion

Elimination occurs from central compartment

Movement of drug between compartments is defined by characteristic first order rate constant
denoted by later K.

The number of rate constant in a particular compartment model is given by R.

For IV administration R = 2n – 1

For extravascular administration R = 2n

Where, n = number of compartments

❖ Various mammary models:

2).Catenary Model

In this model compartment are joined together to one another in a series just like compartment of
train

This is however not observable physiologically/ anatomically, the various organs are directly linked
the blood compartment

Hence, this is rarely used

NON-CONPARTMENT MODEL
Also know as model-independent-method.

Based on the assumption that the drugs or metabolites follow linear kinetics.

It dose not require the assumption of specific compartment model.

Applicable to any compartment model.

Describe the pharmacokinetics of drug disposition using time and concentration parameters

The non-compartmental approach, based on statistical moments theory.

If one considers the time course of drug concentration in plasma as a statistical distribution curve

MRT mean residence time (defined as the average of time spent by the drug in the body before its
elimination)

AUMC area under the first-movement curve

AUC= area under the zero-movement curve

Advantages

• Pharmacokinetic parameters can be easily derived.

• A detailed description of drug disposition is not required.
• Applicable for any drug or metabolite which follow first-order kinetics.

Disadvantage

Provide limited information regarding the plasma drug concentration-time profile.

This method does not adequately treat non-linear cases.

PHYSIOLOGICAL MODEL

Blood flow rate limited and model perfusion rate limited model

Also known as physiologically-based pharmacokinetic models (PB-PK models).

It describes the drug disposition in terms of realistic physiological parameters.

Number of compartments in the model depends upon the disposition in various organs & tissue

Tissue/Organs such as bone that have no drug penetration are excluded.

Highly polar, ionized and charged drugs reffered as membrane permeation rate limited

RET (Rapidly equilibrating tissue) SET(Slowly Equilibrating tissue)

Highly perfused Low perfused
Lungs, liver, brain & kidney Muscles and adipose tissue.

Further categorised into two types-

1).Blood flow rate limited models

• Easy and commonly used model

• k/as perfusion rate limited model

• Because drug movement within the body region is very rapid by the perfusing blood.

• Applicable only for highly membrane permeable drug i.e. low Mw, pooriy ionised and highly
lipophillic drugs

2).Membrane permeation rate limited models-

• Complex model

• k/as diffusion limited model

• Because the cell membrane acts as a barrier for the drug that gradually permeates by diffusion.

• Applicable to highly polar, ionised and charged drugs.

MULTI COMPARTMENT MODELS

Introduction

➤ One compartment is described by mono- exponential term i.e. elimination.

➤ For large class of drugs this terms is not sufficient to describe its disposition.

➤ It needs a bi- or multi- exponential terms

➤ The body is composed of a heterogeneous group of tissues each with different degree of blood flow
and affinity for drug and therefore different rates of elimination.

➤ Multi-compartment characteristics are best described by administration as i.v. bolus.

Two Compartment Model

The simplest and commonest is the two compartment model which classifies the body tissues in two
categories:

1. Central compartment or Compartment 1.

2. Peripheral or Tissue Compartment or Compartment 2.

➤ Compartment 1 comprises of blood and highly perfused tissues like liver, lungs, kidneys, etc.

➤ Elimination usually occurs from this compartment.

➤ Compartment 2 comprises of poorly perfused and slow equilibrating tissues such as muscles,
skin, adipose, etc.

Depending upon the compartment from which the drug is eliminated, the 2 compartment model
can be further categorized into:

1).With elimination from Central compartment.

2).With elimination from peripheral compartment.

3).With elimination from both the compartments.

Two compartment open model – I.V. Bolus Administration

➢ Elimination from central compartment

➢ After the iv bolus of a drug the decline in the plasma conc. Is bi-exponential.
➢ Two disposition processes- distribution and elimination.
➢ These two processes are only evident when a semi log plot of C vs t is made.
➢ Model Structure for Two Compartment Model.
The rate change in drug concentration in the central compartment is given by

Two compartment open model-I.V. Infusion

The plasma or central compartment concentration of a drug when administered as constant rate(0
order) i.v.infusion is given as:

At steady state the second and the third term in the bracket becomes zero and the equation reduces
to: Now, The loading dose

The loading dose,

Two compartment open model- E.V.administration

➢ First order absorption

➢ The model can be depicted as follows

➤ The rate of change in drug conc. In the central compartme described by three exponents: An
absorption exponent

➤ Two usual exponents that describe drug disposition.

➤ The plasma conc, at time t is,

C= Absorption exponent+Distribution exponent+Elimination exponent

Where ,L,M & N are Coefficient

 Nonlinear Pharmacokinetics
• Non-linear pharmacokinetics is observed in some drugs where increase in dosed or chronic
medication can cause deviation from the linear pharmacokinetics profile so it is known as
Dose Dependent Kinetics.
• At lower dose, drug shows first order kinetics but at higher dose, it shows zero order due To
saturation, so it is also known as Mixed Order Kinetics.

Linear pharmacokinetics: - Pharmacokinetic parameters for a drug would not change when
different doses or multiple doses of a drug were given.

Non linear pharmacokinetics:- Pharmacokinetic parameters change with the size of

administered dose.

Differences between Linear and Non Linear Kinetics

Detection of Non Linearity

1. Determination of steady state plasma concentration at different doses: when steady state
plasma concentration is directly proportional to dose (Css ∝ dose) then linearity exist.
2. Determination of some of important pharmacokinetic parameters at different doses: Fraction
biovavailible, t1/2 (half life), ClT(Total systemic clearance) any change in these parameters
indicative of nonlinearity.

Causes of Non Linearity

Drug absorption

1. When absorption is solubility or dissolution rate limited, E.g: Griseofulvin

2. When absorption involves carrier mediated transport system, E.g: Absorption of riboflavin,
Ascorbic acid, Cyanocobalamine
3. When presystemic gut wall or hepatic metabolism attains saturation,E.g: Propranolol,
Hydralazine and Verapamil
4. Changes in gastric emptying and GI blood flow also cause nonlinearity

Drug distribution

1. Saturation of binding sites on plasma proteins, E.g: Phenyl butazone, Naproxen

2. Saturation of tissue binding sites E.g: Thiopental, Fentanyl
Drug metabolism

1. Capacity limited metabolism due to enzyme or cofactor saturation,E.g: Phenytoin, Alcohol &
Theophylline
2. Enzyme induction, E.g: Carbamazepine
3. Saturation of binding sites, inhibitory effect of metabolism on enzyme and pathological
situation and changes in hepatic blood flow

Drug Excretion

1. Active tubular secretion E.g: Penicillin G

2. Active tubular reabsorption E.g: Glucose & water soluble vitamin
3. Forced diuresis , changes in urine pH, nephrotoxicity & saturation of binding sites

Michaelis Menten Equation

➢ Also Known as Line Weaver Burk Plot
➢ Non-Linear Pharmacokinetics can be best described by Michaelis menten equation
➢ The elimination of drug and kinetics of capacity- limited or saturable process is best
described by Michaelis-Menten equation

Where, -dC/dt= Rate of decline of drug concentration with time

Vmax= Theoretical maximum rate of process
Km= Michaelis Constant

Three situation can now be considered depending upon on the values of Km and C

1).When Km = C

➢ The rate of process is equal to half of its maximum rate (Mixed order rate at intermediate doses

➢ This process is represented in the plot of dc/dt vs C shown in figure.

2).When Km >> C

➢ First order rate at low doses (initial rate increases linearly)

3).When Km << C

➢ Zero order rate at higher doses (Rate Process is independent of drug concentration)

E.g: Metabolism of Ethanol

Estimation of Km and Vmax ( IV Bolus )

1).Integration of Michaelis menten equation

2).Semi log plot of C vs. T yields a curve with terminal linear portion, which on back extrapolation to
time zero give y intercept log Co.

3).At low plasma concentrations

Other Plots and their equations:

Drug interactions
Introduction

When the pharmacological activity of a drug is altered by the concomitant use of another drug or by
the presence of some other substance.

The drug whose activity is affected by such an interaction is called as the object drug.

The agent which precipitates such an interaction is referred to as the precipitant.

Drug interactions include:

1. Drug-drug interactions.
2. Food-drug interactions, for example, inhibition of metabolism of several drugs by grapefruit
juice.
 3. Chemical-drug interactions, for example, interaction of a drug with alcohol, tobacco or
environmental chemicals.
4. Drug-laboratory test interaction, for example, alteration of diagnostic laboratory test results by
the presence of drug.
5. Drug-disease interactions, for example, worsening of disease condition by the drug.

Factors Contributing to Drug Interactions Some of the more important risk factors that lead to
drug interactions include:

1. Multiple drug therapy

2. Multiple prescribers
3. Multiple pharmacological effects of drug
4. Multiple diseases/Predisposing illness
5. Poor patient compliance
6. Advancing age of patient
7. Drug related factors

Protein binding of Drugs

➢ The phenomenon of complex formation with protein is called protein binding of
drugs
➢ The formation of a drug- protein complex is often named drug-protein binding
Protein binding may be divided into-

1).Intracellular binding- Drug bind to cell protein produce Pharmacological response

2).Extracellular binding -Drug bind to Extracellular protein doesn’t Pharmacological response

Mechanism of protein binding

Reversible- Drug bind to protein with weak chemical bond

Irreversible- Drug bind to protein with strong covalent bond

Binding of Drugs to Blood Components

Order of plasma proteins binding

Effect of tissue- binding interactions
a).Apparent volume of distribution (Vd): It is defined as the hypothetical volume of body fluid into
which a drug is dissolved or distributed

That would be necessary to contain the total amount of an administered drug at the same
concentration that it is oberserved in the blood plasma

b). Effect of Protein Binding on Apparent Volume of Distribution:

Highly Bound Drugs* Less Bound Drugs*

Stay mostly in the blood Spread more easily to other tissues
Don’t spread much to other tissues Can reach higher concentrations in tissues
Have a smaller “apparent volume of Have a larger “apparent volume of distribution”
distribution”

c). Effect of protein binding on elimination

Highly bound drugs are eliminated slowly, while less bound drugs are eliminated quickly.

d). Effect of protein binding on patient with kidney disease

In patients with kidney disease, protein binding can increase the risk of drug toxicity due to reduced
elimination.

e). Effect of protein binding on patient with hepatic disease

In patients with liver disease, protein binding can be reduced, leading to increased levels of free
(active) drug, which can increase the risk of adverse effects.

Effect of tissue- binding interactions ( tissue localised of drugs)

1).It is 40 % of body weight and 100 times that of HSA

2).Irreversible-Binding involve strong covalent bond

3).Large Volume of distribution.

4). Halt Life of Extravascular tissue Bound drug is relatively long

5).Toxicity is common

6).Displacement generally does not occur

7).Tissue drug binding is generally non competitive

E.g. oxidation product of paracetamol,phenacetin, chloroform, carbon tetrachloride, and bromo

benzene bind covalently
Factors influencing localization of drugs in tissues include:

1. Lipophilicity and structural features of the drug,

2. Perfusion rate,
3. pH differences, etc.

Extensive tissue-drug binding suggests that a tissue can act as the storage site for drugs. Drugs that
bind to both tissue and plasma components result in competition between drug binding sites.

For majority of drugs that bind to extravascular tissues, the order of binding is:

Liver > Kidney > Lung > Muscles

Several Examples of Extra vascular Tissue-drug Binding are:

1. Liver: Paracetamol bind irreversibly to liver tissues resulting in hepatotoxicity.

2. Lungs: Basic drugs like imipramine, chlorpromazine and antihistamines accumulate in lungs.
3. Kidneys: Metallothionin, a protein present in kidneys, binds to heavy metals such as lead,
mercury, and cadmium and results in their renal accumulation and toxicity.
4. Skin: Chloroquine and phenothiazines accumulate in skin by interacting with melanin.
5. Eyes: The retinal pigments of the eye also contain melanin. Binding of chloroquine and
phenothiazines to it is responsible for retinopathy.
6. Hairs: Arsenicals, chloroquine and phenothiazines are reported to deposit in hair shafts.
7. Bones: Tetracycline is a well-known example of a drug that binds to bones and teeth.
Administration of this antibiotic to infants or children during odontogenesis results in
permanent brown-yellow discoloration of teeth.
8. Fats: Lipophilic drugs such as thiopental and the pesticide DDT accumulate in adipose tissues
by partitioning into it.
9. Nucleic Acids: Molecular components of cells such as DNA interact strongly with drugs like
chloroquine and quinacrine resulting in distortion of its double helical structure.