Definition and Introduction to Pharmacokinetics

Definition of Pharmacokinetics: It is defined as the kinetics of drug absorption,

distribution, metabolism, and excretion (ADME) and their relationship with the
pharmacological, therapeutic, or toxicological response in man and animals.

Plasma Drug Concentration-Time Profile

A plasma concentration-time graph shows how the drug levels change in the blood over
time. It helps understand two key factors:

1. How the drug moves in the body (pharmacokinetics)

2. How it affects the body (pharmacodynamics).

This graph is created by measuring the drug amount in blood at different times and
plotting it against time.

Graph: A typical plasma concentration time profile showing pharmacokinetic and

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

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

1. Peak Plasma Concentration (Cmax)

i. 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.
ii. It is also called as peak height concentration and maximum drug concentration.
iii. Cmax is expressed in mcg/ml.
iv. The peak plasma level depends upon the administered dose, rate of absorption, and
rate of elimination.
v. The peak represents the point of time when absorption rate equals elimination rate
of drug.
vi. The portion of curve to the left of peak represents absorption phase i.e. when the
rate of absorption is greater than the rate of elimination.
vii. The section of curve to the right of peak generally represents elimination phase i.e.
when the rate of elimination exceeds rate of absorption.
viii. Peak concentration is often related to the intensity of pharmacological response and
should ideally be above minimum effective concentration (MEC) but less than the
maximum safe concentration (MSC).

2. Time of Peak Concentration (tmax)

i. The time for drug to reach peak concentration in plasma (after extravascular
administration) is called as the time of peak concentration.
ii. It is expressed in hours and is useful in estimating the rate of absorption. Onset time
and onset of action are dependent upon tmax.

3. Area Under the Curve (AUC)

i. AUC (Area Under the Curve) shows the total amount of drug that enters the
bloodstream over time after taking it.
 ii. It is measured in mcg/ml × hours.
iii. AUC helps determine how much of the drug is absorbed and is especially important
for medications taken regularly, like those for asthma or epilepsy.

Pharmacodynamic Parameters

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. The concentration of drug
below MEC is said to be in the sub-therapeutic level.

2. Maximum Safe Concentration (MSC): Also called as minimum toxic concentration

(MTC), 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 MEC.

4. Onset Time: It is the time required for the drug to start producing pharmacological
response. It corresponds to the time for the 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 the MEC level is called as duration of drug 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. It is also known as therapeutic window.

8. Therapeutic Index: The ratio of MSC to MEC is called as therapeutic index. It is also
defined as the ratio of dose required to produce toxic or lethal effects to dose required
to produce therapeutic effect.
 Advantages and applications of compartment modeling

1. It helps track drug movement in the body, including absorption, distribution, and

elimination.

2. It shows different rate processes involved in drug movement.

3. It helps determine how many rate constants are needed for describing drug behavior.

4. It allows writing equations to predict drug concentration changes in the body.

5. Only plasma or urine data is enough to track drug concentration changes.

6. It helps predict drug concentration over time in normal and diseased conditions.

7. It aids in designing proper dosage regimens.

8. It relates plasma drug levels to drug effects both therapeutic and toxic effects.

9. It is useful for comparing different drugs in clinical settings.

10. It simplifies the calculation of key parameters like volume of distribution (Vd) and half-

life (t½).
Advantages of Physiological Modeling:

1. Easier mathematical treatment.

2. Useful when tissue drug concentration and binding are known.

3. Predicts drug levels based on organ size, blood flow, and partition coefficient.

4. Provides a clear drug concentration-time profile in tissues.

5. Helps assess drug behavior in altered conditions.

6. Useful in Animal Studies – Allows invasive sampling for better analysis.

7. Cross-Species Correlation – Data from animals can sometimes predict human drug
behavior.

8. Helps understand absorption, distribution, metabolism, and excretion.

Disadvantages of Physiological Modeling:

1. Complex Data Collection – Requires extensive experimental work.

2. Assumptions on Blood Flow – Limits personalized dosing.

3. Limited Data Points – Fewer data points than required for full assessment.

4. Difficult Monitoring – Needs large amounts of data for accurate predictions.

 Distributed Parameter Model

This model is analogous to physiological model but has been designed to take into account

 Variations in blood flow to an organ, and

 Variations in drug diffusion in an organ.

Such a model is thus specifically useful for assessing regional differences in drug
concentrations in tumors or necrotic tissues.

The distributed parameter model is more complex than physiological models because it
uses difficult mathematical equations and obtaining drug concentration data is difficult.

Noncompartmental analysis

 The noncompartmental analysis, also called as the model-independent method

 Does not require the assumption of specific compartment model.
 Based on the assumption that the drugs or metabolites follow linear kinetics.

Noncompartmental analysis approach is based on statistical moments theory. It is a

method used to analyze drug concentration over time, like finding the average time a drug
stays in the body before being eliminated (MRT).

MRT = AUM / AUC

MRT = mean residence time

AUMC = area under the first-moment curve

AUC = area under the zero-moment curve

AUMC is obtained from a plot of product of plasma drug concentration and time (i.e. C.t)
versus time t.
AUC is obtained from a plot of plasma drug concentration versus time.

Practically, the AUMC and AUC can be calculated from the respective graphs by the
trapezoidal rule (the method involves dividing the curve by a series of vertical lines into a
number of trapezoids, calculating separately the area of each trapezoid and adding them
together).

Applications

Used to estimate pharmacokinetic parameters like bioavailability, clearance , V d, half-life,

first order absorption rate constant of the drug.

Advantages

1. Ease of derivation of pharmacokinetic parameters by simple algebraic equations.

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

1. It provides limited information regarding the plasma drug concentration-time profile.

2. More often, it deals with averages.
3. The method does not adequately treat non-linear cases.
 KE (Elimination rate constant)

Definition

 KE is a number that tells us how quickly a drug is removed from the body.
 It is usually expressed in per hour (h⁻¹).
 It is based on first-order kinetics, where a constant fraction (not amount) of drug is
removed per unit time.
 Mathematically:

𝑑𝐶
= −𝐾𝐸 ⋅ 𝐶
𝑑𝑡
where C is the concentration and dC/dt is the rate of change.

 It’s obtained from the slope of the log plasma concentration vs. time curve:

𝐾𝐸 = −slope × 2.303

Significance
 A higher KE means the drug is eliminated faster, while a lower KE means the drug
stays in the body longer.
 Understanding KE helps in determining how frequently a drug should be administered
so that therapeutic levels are maintained without causing toxicity.
 People with kidney or liver issues may have altered KE values, requiring dose changes.

Application:
 Half-life calculation:

0.693
𝑡1/2 =
𝐾𝐸
This helps decide how often to give a drug.

 Concentration of drug at any time can be calculated using the formula

𝐶𝑡 = 𝐶0 ⋅ 𝑒 −𝐾𝐸⋅𝑡

 Used in loading dose, maintenance dose, and dosing interval planning.

 If drug elimination slows (KE decreases), drug accumulation and toxicity may occur
knowing KE helps prevent this.
 Ka (Absorption rate constant)

Definition

 It tells us how quickly a drug enters the bloodstream from the site of administration
(like the stomach or intestine).

 It applies to extravascular routes (oral, subcutaneous, intramuscular—not IV).

 Units: per hour (h⁻¹)

Significance of Ka

 Tells how fast the drug is absorbed into the blood after taking it by mouth or other
non-IV routes.

 If Ka is high, the drug enters the blood quickly and acts faster.

 If Ka is low, the drug takes longer to start working.

 Helps us understand when the drug will reach its peak effect.

 Important in checking how food or other drugs may slow down or speed up
absorption.

Application of Ka

 Helps decide whether to use a fast-acting tablet (like painkillers) or a slow-release

formulation (like once-a-day tablets).

 By knowing Ka, we can choose how often a drug should be taken to maintain steady
levels in the body.

 Ka helps estimate how soon the drug will start working after administration —
important for urgent conditions.

 Some foods slow down drug absorption. Ka helps study and adjust timing of medicine.

 Pharmaceutical scientists use Ka to develop better drug products that absorb

efficiently and give consistent results.
 Clearance (Cl)

Clearance is the volume of blood (or plasma) from which a drug is completely removed
per unit time.

Units: mL/min or L/hr

Clearance (Cl) = Rate of drug elimination / Plasma drug concentration

Types of Clearance

 Renal Clearance – by kidneys

 Hepatic Clearance – by liver
 Pulmonary Clearance – by lungs
 Total Clearance = sum of all clearances

Renal Clearance

Definition: It is the volume of blood or plasma that is completely cleared of the drug by
the kidneys in one minute.

ClR = Rate of urinary excretion / Plasma drug concentration

Renal Clearance Ratio (Excretion Ratio)

This helps to understand how the kidney is handling a drug — just filtering it or also
reabsorbing or secreting it.

Renal Clearance Ratio = ClR of drug / ClR of creatinine

If Ratio =

 1 → only filtration

 <1 → filtration + reabsorption

 >1 → filtration + secretion

Significance of Renal Clearance (CLR)

 Helps assess kidney function in clearing drugs.

 Higher CLR means the kidneys are removing the drug quickly.

 Lower CLR means drug stays longer in the body, which can lead to drug buildup and
toxicity, especially in patients with kidney problems.

Application of Renal Clearance (CLR)

 If a patient has renal impairment, their CLR will decrease, so the drug dose may need to
be reduced to avoid toxicity.

 Drugs like lithium or digoxin, which are mainly eliminated by the kidneys, are
monitored for renal clearance to prevent accumulation.

 Helps estimate how much of a drug will be excreted in urine and how often it should be
administered.

Total Clearance (Clt)

 Definition: It is the overall volume of plasma from which a drug is completely removed
per unit of time, accounting for all routes of elimination: kidneys, liver, lungs, etc.

 It combines the contributions from renal clearance (CL R) and hepatic clearance (from
the liver) or other pathways.

Clt = ClR+ ClH + Clother

Significance of Total Clearance (Clt)

 Total clearance tells us the overall efficiency of the body in eliminating the drug.

 Higher Clt means the drug is eliminated more quickly, and lower Clt means the drug
stays in the body longer.

 It’s crucial for understanding how frequent dosing should be.

 Application of Total Clearance (Clt)

 If a drug has a high Clt, it may need to be taken more often, whereas a drug with low Clt
may require less frequent dosing.

 Drugs that affect hepatic or renal function can change Clt and thus influence the
required dose. For example, drugs that inhibit the liver can slow the clearance of other
drugs processed by the liver.

 Helps doctors understand how quickly a drug should be removed from the body, so
they can adjust the dose size and frequency to maintain effective drug levels.

t½ (half-life)
Definition: t½ is the time in which the amount of drug in the blood reduces to half of its
original value.

If a drug's t½ is 4 hours, and you have 100 mg in your body:

 After 4 hours → 50 mg

 After 8 hours → 25 mg

 After 12 hours→12.5mg…and so on.

Formula: t ½ = 0.693/Ke

Significance

1. Tells how long the drug stays in the body

2. Helps determine dosing frequency (how often to give the drug)

3. Helps predict when the drug reaches steady-state during repeated doses

4. Useful in planning drug withdrawal before surgery, pregnancy, etc.

Applications
1. Dosing schedule:
  Short t½ → drug is given more frequently

 Long t½ → drug is given less frequently

2. Therapeutic drug monitoring: Used to decide when to check blood levels of a drug.

3. Washout period: Helps in deciding how long to wait before starting a new drug.

4. Comparing drugs: Drugs with longer half-life act longer, but may take more time to be
removed from the body.

Vd (Volume of Distribution)
Definition: Vd is a hypothetical volume that tells us how the drug is distributed in the
body compared to the blood.

It shows how much drug has moved out of the blood and into the tissues (like fat, muscles,
organs).

Formula

Vd= Amount of drug in the body / Plasma drug concentration

Significance
1. Tells where the drug is going:

 Low Vd → drug mostly stays in the blood

 High Vd → drug moves into tissues

2. Helps in deciding the loading dose (the first higher dose to quickly reach desired
levels)

3. Tells us about the lipophilicity (fat-loving nature) of the drug: Lipophilic drugs →
higher Vd (they go into fat tissues)

Applications
1. To calculate loading dose: Loading dose = Vd × Desired plasma concentration
2. To understand drug distribution: Example: If Vd is very large, it means most of the
drug is not in the blood — it’s hiding in fat or tissues.

3. Helps in the treating poisoning cases:

Low Vd = poison is in the blood = easier to remove.

High Vd = poison is hiding in tissues = harder to remove.

AUC (Area Under the Curve)

Definition: It is the total area under the plasma concentration vs. time graph after a drug
is given.

AUC tells us how much of the drug was present in the body over time

Units of AUC: mg.hr/L

Significance
1. Measures total drug exposure: Higher AUC = more drug available in the body over
time

2. Helps compare drug formulations: Used to check bioequivalence between two drug
products (same AUC = same effectiveness)

3. Assesses how well a drug is absorbed: If a drug has poor absorption, the AUC will be
low
4. Used in calculating clearance: Cl=Dose/ AUC

Applications
1. Bioavailability studies:

 AUC helps compare oral vs. IV drug absorption.

 IV gives 100% bioavailability → used as reference.

2. Therapeutic drug monitoring (TDM): For drugs with a narrow therapeutic window
(e.g., phenytoin, vancomycin), AUC helps avoid toxicity.

3. Drug comparison: If two drug brands have similar AUC, they are considered
bioequivalent.

4. In toxicity and overdose: A very high AUC may mean the drug is staying too long and
may cause harm.