PHARMACOKINETICS

Syllabus:

(a) Introduction to various pharmacokinetic parameters:

(i) Biological half-life

(ii) Apparent volume of distribution

(iii) Clearance

(iv) Rate constants for elimination

(b) Introduction to different models and study of model one and two.

PHARMACOKINETICS

Pharmacokinetics is the study of those rate processes involved in the absorption, distribution, metabolism, and excretion of drugs and their relationship to the pharmacological, therapeutic, or toxic response in animals or humans.

When a drug is administered in a dosage form

* first it is absorbed from its site of administration,

* reaches the blood circulation,

* distributed all over the body,

* drug molecules reaches the site of action,

* some drug molecules are metabolized and

* ultimately the drug molecules are eliminated from the body.

Pharmacokinetic techniques attempt to mathematically define the time course for drug in the body by assaying for drug and metabolites in readily accessible fluids.

PHARMCOKINETICS

Drug in Drug at Drug in Drug

Dosage absorption blood excreted

Form site and metabolized

Drug distributed

through out the body

BIOPHARMACEUTICS DISPOSITION

Scheme-I

As illustrated in Scheme-I, pharmacokinetics includes the study of all of the controlling rate processes. It is sometimes called ADE kinetics [i.e. absorption, distribution, and elimination kinetics]; sometimes ADME also [i.e. absorption, distribution, metabolism and elimination kinetics].

Biopharmaceutics considers the interrelationship of the physicochemical properties of the drug, the dosage form, and the route of administration on the rate and extent of drug absorption.

Thus biopharmaceutics involves factors that involves the

1. protection of the activity of the drug within the product

2. the release of the drug from a product,

3. the rate of dissolution of the drug at the absorption site, and

4. the systemic absorption of the drug.

Disposition deals with the kinetics of distribution and elimination. [i.e. DE kinetics)

Once absorbed the drug is subject only to DE kinetics.

Any or all of the ADE rate processes may be influenced by the physicochemical properties of the drug and the health, age, and sex of the patient.

Clinical pharmacokinetics is the application of pharmacokinetic methods in drug therapy.

It involves a multidisciplinary approach to individualistic optimized dosing strategies based on the patient’s state and patient specific consideration.

Age, gender, genetic, and ethnic differences can also result in pharmacokinetic differences that may affect the outcome of a drug therapy. The study of pharmacokinetic differences of drugs in various population groups is termed population pharmacokinetics.

When drugs with narrow therapeutic indices are used in patients, it is necessary to monitor plasma drug concentrations closely by taking periodic blood samples. This type of monitoring is called therapeutic drug monitoring (TDM). Some drugs frequently monitored are amino glycosides, anticonvulsants and anticancer drug to reduce the side effects.

Pharmacodynamics refers to the relationship between the drug concentration at the site of action (receptor) and pharmacological response, including biochemical and physiological effects that influence the interaction of drug with the receptor.

The interaction of a drug molecule with the receptor initiates a sequence of molecular events resulting in a pharmacological or toxicological responses. Pharmacokinetic–Pharmacodynamic models are constructed to relate plasma drug concentrations at the site of action and establish the intensity and time course of the drug.

Toxicokinetics is the application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies in validating dose related exposures in animals. Toxicokinetic data obtained from animals are extrapolated to humans.

Toxicokinetic studies are performed in animals during preclinical drug development and may continue after the drug has been tested in clinical trials.

DRUG DISPOSITION

Plasma drug concentration - Time Profile

When a drug is administered to any site (e.g. oral administration) the drug is absorbed from the site of administration, then it is distributed all over the body, finally it is eliminated. If time to time blood samples are drawn, and the plasma concentration of unchanged drug in the blood (or plasma) is plotted versus time then the following graph may be obtained.

Fig. A typical plasma concentration-time profile of a drug

The three important pharmacokinetic parameters those describe the plasma level-time curve and useful in assessing the bioavailability of a drug from its formulation are:

1. Peak plasma concentration (C_max)

The point of maximum concentration of drug in plasma is called as the peak and the concentration of drug at peak is known as peak plasma concentration.

Before the peak : absorption rate > elimination rate

At the peak: absorption rate = elimination rate

After the peak : absorption rate < elimination rate.

The peak plasma concentration should always remain above MEC to get a pharmacological response.

2. Time of peak concentration (t_max)

The time for drug to reach peak concentration in plasma is called the time of peak concentration.

3. Area under the curve (AUC)

AUC represents the total integrated area under the plasma level-time profile.

It expresses the total amount of drug that comes into the systemic circulation after its administration.

Unit of AUC : (micrograms / ml) x hours

Significance: It is the most important parameter in evaluating the bioavailability of a drug from its dosage form as it represents the extent of absorption. AUC is also important for drugs that are administered repeatedly for the treatment of chronic conditions like asthma or epilepsy.

The various pharmacodynamic parameters are :

1. Minimum effective concentration (MEC)

It is defined as the minimum concentration of drug in plasma required to produce the therapeutic effect. In case of antibiotics, the term minimum inhibitory concentration (MIC) is used. It describes the minimum concentration of antibiotic in plasma required to kill or inhibit the growth of microorganisms.

2. Maximum Safe Concentration (MSC)

Also called minimum toxic concentration.

It is the concentration of drug in plasma above which adverse or unwanted effects are precipitated. Concentration of drug above MSC is said to be in the toxic level.

3. Onset of Action

The beginning of pharmacological response is called as onset of action. It occurs when the plasma drug concentration just exceeds the required minimum effective concentration (MEC).

4. Onset time

It is the time required for the drug to start producing pharmacological response. It corresponds to the time for plasma concentration to reach MEC after administration of drug.

5. Duration of Action

The time period for which the plasma concentration of drug remains above MEC level is called as duration of action.

6. Intensity of action

It is the maximum pharmacological response produced by the peak plasma concentration of drug. It is also called as peak response.

7. Therapeutic Range

The drug concentration between MEC and MSC represents the therapeutic range.

BASIC PHARMACOKINETIC MODELS

A model is a hypothesis using mathematical terms to describe quantitative relationships. Various mathematical models can be devised to simulate the rate processes of drug absorption, distribution, and elimination. This mathematical models make possible the development of equations to describe drug concentrations in the body as a function of time.

Pharmacokinetic models are used to:

1. Predict plasma, tissue and urine drug levels with any dosage regimen.

2. Calculate the optimum dosage regimen for each patient individually.

3. Estimate the possible accumulation of drugs and / or metabolites.

4. Correlate drug concentrations with pharmacological or toxicological activity.

5. Evaluate differences in the rate or extent of availability between formulations (bioequivalence).

6. Describe how changes in physiology or disease affect the absorption, distribution, or elimination of the drug.

7. Explain drug interaction.

COMPARTMENTAL MODELS

Here the body is considered as composed of several compartments that communicate reversibly with each other.

N.B. If one considers every organ, tissue or body fluid that can get equilibrated with the drug as compartments, then infinite number of compartments can exist in the body and the mathematical description of such a model will be too complex to be handled. Hence, tissues which are approximately similar in their drug distribution characteristics are pooled to form a kinetically homogeneous hypothetical compartment.

Such a compartment is not a real physiologic or anatomic region but a fictitious or virtual one.

The kinetics of most drugs can be described by a hypothetical model consisting of one, two or at the most three functional compartments arranged either in series or parallel to each other.

** It is also assumed that the rate of drug movement between compartments (i.e. entry and exit) follow first-order kinetics.

Depending upon whether the compartments are arranged parallel or in a series, compartment models are divided into two categories - mammillary model and caternary model.

Mammillary model

· This model is the most common compartment model used in pharmacokinetics. It consists of one or more peripheral compartments connected to the central compartment in a manner similar to connection of satellites to a planet.

· The central compartment (or compartment -I) comprises of plasma and highly perfused tissues such as lungs, liver, kidneys, etc. which rapidly equilibrate with the drug.

· The peripheral compartments or tissue compartments (denoted by numbers 2,3, etc.) are those with low vascularity and poor perfusion. Distribution of drugs to these compartments is through blood.

· Movement of the drug between compartments is defined by characteristics first-order rate constants denoted by letter K. The subscript indicates the direction of drug movement. Thus K₁₂ refers to drug movement from compartment 1 to 2 and reverse for K₂₁.

Model-1 One-compartment open model, intravenous administration

I K₁₀

Model-2 One-compartment open model, extra-vascular administration

K₀₁I K₁₀

Model-3 Two-compartment open model, intravenous administration

K₁₂

1 2

K₂₁

K₁₀

Model-4 Two-compartment open model, extravascular administration

K₁₂

K₀₁ 1 2

K₂₁

K₁₀

Model-5 Three-compartment open model, intravenous administration

K₁₂ K₂₁

K₁₃

1 3

K₃₁

K₁₀

Model-6 Three-compartment open model, extravascular administration

K₁₂ K₂₁

K₁₃

K₀₁ 1 3

K₃₁

K₁₀

For intravenous administration

Number of compartments	Rate constants	Number of rate constants
1 2 3	K₁₀ K₁₀, K₁₂, K₂₁ K₁₀, K₁₂, K₂₁, K₁₃, K₃₁	1 3 5

For extarvascular administration

Number of compartments	Rate constants	Number of rate constants
1 2 3	K₁₀, K₀₁ K₁₀, K₀₁, K₁₂, K₂₁ K₁₀, K_01, K₁₂, K₂₁, K₁₃, K₃₁	2 4 6

So the number of rate constants that will appear in a particular compartment model is given by R, where

For intravenous administration, R = 2n - 1

For extravascular administration, R = 2n where, n = the number of compartments.

Advantages of compartmental modeling

1. It gives a visual representation of various rate processes involve in drug disposition.

2. It show hoe many rate constants are necessary to describe these processes.

3. It enables the pharmacokineticist to write differential equations for each of the rate processes in order to describe drug-concentration changes in each compartment.

4. It is useful in predicting drug concentration-time profile in both normal physiological and i pathological conditions.

5. It is important in the development of dosage regimens.

Disadvantages of compartmental modeling:

1. The compartments and parameters bear no relationship with the physiologic functions or the anatomic structure of the species; several assumptions have to be made to facilitate data interpretation.

2. Extensive efforts are required in the development of an exact model that predicts and describes correctly the ADME of a certain drug.

3. The model is based on curve fitting of plasma concentration with complex multi-exponential mathematical equations.

4. The model may vary within a study population.

5. The approach can be applied only to a specific rug under study.

6. The drug behavior within the body may fit different compartmental models depending on the route of administration.

Difficulties generally arise when using models to interpret the differences between results from human and animal experiments.

Catenary model

In this model, the compartments are joined to one another in a series like compartments of a train. This is not observable physiologically / anatomically as the various organs are directly linked to the blood compartment. Hence this model is rarely used.

K₀₁ K₁₂ K₂₃

1 2 3

K₂₁ K₃₂

Physiologic Model (Perfusion rate limited model)

The rate of appearance of a drug in a tissue depends on two processes:

(i) perfusion of blood into that tissue and

(ii) permeation of drug from blood capillaries to the tissue fluid

In case of highly membrane permeable drugs e.g. low molecular weight, poorly ionized and highly lipophilic drugs the permeation step is much faster than the perfusion step. Hence the process is called perfusion rate limited (because perfusion step is the slowest step and the over all rate can be controlled by controlling this step only).

Drug concentrations in various tissues are predicted by organ tissue size, blood flow, and experimentally determined drug tissue-blood ratios (i.e. partition of drug between the tissue and blood).

Because there are many tissue organs in the body, each tissue volume must be obtained and its drug concentration is described. Unfortunately, it is difficult to obtain data from different tissue experimentally (the animal or subject should be sacrificed).

NON-COMPARTMENTAL ANALYSIS

The non-compartmental analysis, also called model independent method, does not require the assumption of specific compartment model provided the drugs or metabolites follow linear kinetics.

the approach is based on the statistical moments theory, involves collection of experimental data following a single dose of drug. If one considers the time course of drug concentration in plasma as a statistical distribution curve, then:

where, MRT = mean residence time

AUMC = area under the first-moments curve

AUC = area under the zero-moment curve

Mathematically,

and

Practically, the AUMC and AUC can be calculated from the respective graphs by the trapezoidal rule.

MRT is defined as the average amount of time spent by the drug in the body before being eliminated.

Practically it is the time required for 63.2% of the intravenous bolus dose to be eliminated.

Advantages of non-compartmental analysis:

1. Non-compartmental technique is widely used to estimate the important pharmacokinetic parameters like bioavailability, clearance and apparent volume of distribution. The method is also useful in determining half-life, rate of absorption and first-order absorption rate-constants of the drug.

2. The same mathematical treatment can be applied to almost any drug or metabolite, provided they follow first-order kinetics.

3. A detailed description of drug disposition characteristics is not required.

Disadvantages of non-compartmental analysis:

It provides limited information regarding the plasma drug-concentration-time profile; more often, it deals with averages.

ONE COMPARTMENT OPEN MODEL

Questions:

1. Describe the one compartment open model with mathematical and graphical explanation. (98/s) [16]

2. Write short note on one compartment open model. (96) [4]

· The one-compartment open model is the simplest model which depicts the body as a single, kinetically homogeneous unit that has no barriers to the movement of drug and final distribution equilibrium between the drug in plasma and other body fluids is attained instantaneously and maintained at all the time.

· This model thus applies only to those drugs that distribute rapidly though out the body.

· The concentration of drug in plasma represents the drug concentration in all body tissues.

· The term “open” indicates that the input (availability) and output (elimination) are unidirectional and that the drug can be eliminated from the body.

Fig1. Representation of one-compartment open model showing

input and output process.

Depending upon the rate of input, several one compartment open models can be defined:

(i) intravenous bolus administration

(ii) continuous intravenous infusion

(iii) extravascular zero-order absorption

(iv) extravascular first-order absorption.

Intravenous bolus administration

When a drug that distributes rapidly in the body is given in the form of a rapid intravenous injection (i.e IV bolus dose), it takes about 2 to 3 minutes for complete circulation and therefore the rate of absorption is neglected in calculations. The model can be depicted as follows:

Elimination Rate Constant

Change in amount of drug in the body

where X = amount of drug in the body remained to be eliminated at time, t.

= rate of input - rate of output

= 0 - k_EX ----------(i) where k_E is the first order elimination rate constant

This k_E includes both the rate constants of metabolism (k_m) (or biotransformation) and excretion(k_e) of the drug.

Integrating eqn (i)

ln (X/X₀) = - k_Et ----------------(ii)

Since X = C V_d where V_d is apparent volume of distribution and

C = concentration of the drug in plasma at time t.

Replacing X in equation (i)

ln (C/C₀) = - k_Et

or C/C₀ = e ^{- kE t}

or C = C₀ e ^{- kE t} --------------(iii)

Taking logarithm of eqn (iii)

log C = log C₀ - (k_E / 2.303) t

Constant k_E can be calculated from the slope of fig.2

Slope = - (k_E/2.303)

\ k_E = - 2.303 x Slope

Elimination half life (or Biological half life)

It is defined as the time taken for the amount of drug in the body as well as plasma concentration to decline by one half its initial value.

i.e. at time t = 0 C = C₀.

and at time t = t_1/2

Substituting the values of t and C in the logarithmic form of eqn. (iii) yields:

log (C₀/2) = log C₀ - (k_E / 2.303) t_1/2.

or,

It is expressed by

Apparent volume of distribution (V_d)

The apparent volume of distribution is a parameter of the one-compartment open model because the volume of distribution governs the plasma concentration of the drug after a given dose.

Due to rapid drug equilibration in between the blood and tissues. The volume in which the drug is assumed to be uniformly distributed is termed as the volume of distribution.

The volume of distribution represents a volume that must be considered in estimating the amount of drug in the body from the concentration of drug found in the sampling compartment.

It is actually called the apparent volume of distribution because the value of the volume of distribution does not have a true physiologic meaning in terms of an anatomic space. It is only a hypothetical one.

Method-I

It is determined by administering it by rapid i.v. injection and using the following equation:

The C₀ value is obtained by extrapolation of the plot of log(plasma conc) vs time.

Method-II

V_d can be determined by another way if the AUC and the first order elimination rate constant, k_E is known.

In the equation

the X terms are substituted by X = V_d x C,

where C = plasma concentration of unchanged drug in the body;

we get

Integrating both sides upto infinite time

Since X_µ = 0 hence,

Therefore,

The calculation of V_d by means of the above equation is model independent because no pharmacokinetic model is considered while calculating and the AUC is determined by the trapezoidal rule.

Significance of Volume of distribution

The apparent volume of distribution is not a true physiologic volume. Most drug have an apparent volume of distribution smaller than, or equal to, the body mass.

· From equation,

it is evident that V_d is dependent on C₀. Drugs with a large V_d are more concentrated in the extravascular tissues and less concentrated intravascularly.

Þ When the drug is concentrated in the peripheral tissues the C₀ is small resulting in large V_d.

Þ If a drug is highly bound to plasma proteins or remains in the vascular region, then C₀ will be higher; resulting in a smaller V_d.

· V_d is a volume term that can be expressed as a simple volume or in terms of percent of body weight. In expressing the V_d in terms of % body weight, a 1 L volume is assumed to be equal to the weight of 1 kg. e.g. if the volume of distribution, V_d, is 3500 mL for a subject weighing 70 kg, the V_d expressed as % body weight would be:

If V_d is a large number – i.e. > 100 % of body weight – then it may be assumed that the drug is concentrated in certain tissue compartments. Thus the V_d is a useful parameter in considering the relative amounts of drug in the vascular and in the extravascular tissues.

· Pharmacologists often attempt to conceptualize the V_d as true physiologic or anatomic volume, however this assumption is rarely correct.

· Given the apparent volume for a particular drug, the total amount of drug in the body at any time after administration of the drug may be determined by measuring the plasma concentration according to the following formula:

X = V_d x C

· For each drug the V_d is constant. in certain physiologic cases, the apparent V_d for the drug may be altered if the distribution of the drug is changed.

1. For example in oedematous conditions, the total body water and total extracellular water increase; this is reflected in a large V_d.

2. Similarly. changes in total body weight and lean body mass (which normally occur with age) may also affect apparent V_d.

CLEARANCE

N.B. The body is considered as a system of organs perfused by plasma and both body fluids. Drug elimination from the body is an ongoing process due to both metabolism (i.e. biotransformation) and drug excretion through the kidney and other routes. The mechanisms of drug elimination are complex, but collectively drug elimination from the body may be quantitated using the concept of drug clearance. The rate of elimination may be expressed in several ways, each of which essentially describe the same process, but with different levels of insight and application in pharmacokinetics.

Definition: Clearance is defined as the volume of plasma fluid that is cleared of drug per unit time.

Drug Elimination expressed as Amount Per Unit Time (i.e. Mass approach)

Unit: mg/min or mg/hr

Advantage:

1) The expression of drug elimination from the body in terms of mass per unit time is simple, absolute, and unambiguous.

2) For a zero order elimination process, expressing the rate of drug elimination as mass per unit time is convenient because the rate is constant.

Disadvantage:

1. For a first-order elimination, drug clearance expressed as mass per unit time is not constant.

Drug Elimination expressed as Volume Per Unit Time (i.e. Volume approach)

Unit: ml/min or litre/hr

Advantage:

For a first-order elimination, drug clearance expressed as volume per unit time is constant. This approach of clearance is most common in pharmacy.

N.B. The drug concentration in the body will gradually decline such that the mass of drug removed over time is not constant. The plasma volume in the healthy state is relatively constant because water lost through the kidney is rapidly replaced with fluid absorbed from the gastrointestinal tract.

Therefore

The negative sign refers to the drug exiting from the body.

Clearance from drug eliminating tissues:

Clearance may be applied to any organ that is involved in drug elimination from the body.

Elimination of drug from the body involves

(a) excretion through kidney,

(b) metabolism in the liver,

(d) excretion through other eliminating organs.

Clearance at an individual organ level is called as organ clearance. It can be estimated by dividing the rate of elimination by each organ with the concentration of drug present in it. Thus,

Other organ clearance,

The total body clearance (CL_T) also called as total systemic clearance, is the sum of all the organ clearances, provided all the elimination processes are following first order rate process.

Hence,

Total Systemic Clearance, CL_T = CL_R + CL_H + CL_Others

Non-renal Clearance: clearance by all organs other than kidney is called non-renal clearance CL_NR .

CL_NR = CL_T - CL_R

Following equations can be written for total, renal and hepatic clearances:

CL_T = k_EV_d k_E = overall elimination rate constant

CL_R = k_e V_d k_e = elimination rate constant through renal route

CL_H = k_m V_d k_m = elimination rate constant by metabolism in the liver

Since k_E = 0.693 / t_1/2 where t_1/2 = elimination half-life of the unchanged drug

From the equation CL_T = k_E V_d

CL_T = 0.693 V_d / t_1/2

0.693 V_d

For renal clearance: CL_R =

t_1/2 of urinary excretion

0.693 V_d

For hepatic clearance: CL_H =

t_1/2 of hepatic clearance by metabolism

Determination of clearance values:

· For drugs given as i.v. bolus:

CL_T = X₀/AUC (ml/min)

· For drugs administered extravascularly (e.g. orally)

CL_T = FX₀/AUC (ml/min)

where F = fraction of dose available in the systemic circulation.

· For a drug given i.v. bolus, the renal clearance (CL_R) may be estimated by determining the total amount of unchanged drug excreted in urine, X_U and AUC at infinite time.

Calculation of k_e from urinary excretion data:

The overall elimination rate constant k_E may be calculated from urinary excretion data. In this calculation the excretion rate constant of unchanged drug is assumed to be first order.

.............................. eqn (1)

Where X_U = amount of unchanged drug excreted through urine

X_B = amount of unchanged drug present in the body (or blood)

ke = renal excretion rate constant

From the first order equation of one compartment open model

.....................eqn (2)

Substituting X_B in equation (1) :

Taking the natural logarithm of both sides the following expression is obtained:

................................. eqn (3)

When eqn (3) is plotted it gives a straight line having a slope of k_E and an intercept of ln (k_eX₀).

Thus from the slope k_E is calculated.

Since X₀ is the initial dose of the drug so from the intercept ln (k_eX₀) , k_e can be calculated.

Intercept = ln (k_eX₀)

For non-renal route of excretion

k_NR = k_E – k_e.

However, since the elimination of a drug is usually effected by renal excretion and metabolism (biotransformation) hence k_NR is approximately equal to k_m.

i.e. k_NR » k_m.

AREA UNDER THE CURVE

Definition:

The area under the time course for concentration in plasma from time zero to infinity following a single dose is called the area under the curve (AUC).

Determination:

(a) Calculating AUC values from Time Course Equation for C.

For an equation of the form

C @ C₀ e^-^{l t}.

the area under the curve for C versus t = 0 to t = µ is the integral

which integrates to

AUC =

C₀ e^-^{l t}.dt

AUC = C_o / l

b. Calculating AUC values graphically:

The areas are estimated directly from C- versus t plot. these estimates may be obtained in several ways:

(i) By using planimeter

(ii) By plotting data for C versus t and then cutting out the curve and weighing it. The area may be calculated from the weight of the paper by determining the weight of known area of the same paper cut as a square or a rectangle.

(iii) By trapezoidal method:

In this method the area under the curve is estimated by dividing the curve into sections that approximate a series of trapezoids, where the area of each trapezoid is

. All the area of the trapezoids are then summed to obtain the AUC.

Advantages of graphical methods:

The AUC does not depend upon an equation or compartmental model to adequately describe the data.

ONE COMPARTMENT OPEN MODEL – EXTRAVASCULAR ADMINISTRATION

When a drug is administered by extravascular routes (e.g. oral, intramuscular, rectal etc.) there will be absorption and elimination phase.

From a dosage form drug may be released at the absorption site. The drug may be absorbed in zero-order or first-order kinetics. Rate of change of drug in the central compartment (i.e. blood) =

Where, X = amount of drug present in the body.

= Rate of absorption – Rate of elimination

During absorption phase

At peak plasma concentration

At the elimination phase

Two types of absorption models may be found:

(A) Zero-order absorption model: The rate of drug absorption is constant and continues until the amount of drug present at the absorption site.

Equation:

where k_a , k_E are first order rate constants for absorption and elimination respectively

(B) First order absorption model: In this case the drug is entering into the body following first order kinetics i.e. the rate of absorption is proportional to the concentration of the drug at the site of absorption.

Equation:

where k_a = first order absorption rate constant

Integration of the above equation will yield:

Transforming into concentration terms the equation becomes:

where C = plasma concentration of the drug

k_a = first order absorption rate constant

F = fraction of dose absorbed systmatically after administration

X₀ = dose of the drug administered

V_d = apparent volume of distribution

K_E = overall elimination rate constant (first order)

T = time

Calculation of absorption rate constant

(A) Feathering technique / Method of residual

For a drug that is administered by extra-vascular route the concentration in plasma is expressed by an exponential equation of the form

This equation can be expressed in the form of

where

This equation is a biexponential equation.

Questions:

What are the advantages and disadvantages of compartmental pharmacokinetic models?

What is mean residence time and how you can determine it? What are the advantages and disadvantages of compartmental model?

Describe the one compartment open model with mathematical and graphical explanation

What is apparent volume of distribution? How can you determine it? What are the significances of volume of distribution?

What are the various routes of elimination of a drug from a body? What is the relationship between total clearance and renal clearance of a drug? How do you determine the total clearance of a drug from a body?

What are the various methods of determining the area under the curve of plasma concentration vs. time?

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