Compartment Model Lecture

Model:
• Model is a schematic and easy to understand representation of a
complex phenomenon
• The pharmacokinetic models simplifies the behavior of drug in the body
• Models are based on mathematical relationships and are used and
predict overall bahavior of a drug in the body

Need of using pharmacokinetic models:

• Drug is in dynamic state in the body
• Concentration changes with time
o A
o D
o E
o M
• Acquire drug kinetics in the body

Reliability of the models:

• Hypothesis
• Rarely equate an actual system

Type of pharmacokinetic models:

• Empiric model / classical model
o Divide the body into finite no of compartments in which drug may
distribute itself rapidly
▪ Open Model
• Drug can escape from body
• Generally used
 ▪ Closed Models
• Not used
• Doesn’t allow drug to esacape
• Physiological based models

Compartments:
1. Blood / Central compartment
• Highly perfused tissue
• Heart, lung, endocrine glands
• Highest rate of drug distribution
2. Shallow Tissue Compartment
• Fast exchange with blood
• Skin, adipose tissue and bone marrow
3. Deep tissue compartment
• Slow exchange
• Bone, ligaments and tendons

Characteristics:
• Not real physiological
• Reversible

Functions:
• Enable us to write mathematical / differential equations to describe the
drug conc. Change in each compartment
• Give us the visual representation of the rate process
• Show us how many rate processes are necessary to describe a process
Pharmaceutics – V: Biopharmaceutics and Pharmacokinetics

Unit No. 05

LINEAR AND NON-LINEAR PHARMACOKINETICS

Muhammad Muneeb
_______________________________________________________________________________________

Introduction:
• Pharmacokinetics: It is defined as the kinetics of drug absorption, distribution, metabolism and
excretion and their relationship with the pharmacological, therapeutic or toxicological response in man
and animals.
• Linear pharmacokinetics: Pharmacokinetic parameters for a drug would not change when different
doses or multiple doses of a drug were given.
• Nonlinear pharmacokinetics: Pharmacokinetic parameters change with the size of administered
dose.

Scope of Chrono-pharmacokinetics studies:

• Daily variation in pharmacokinetics
• Narrow therapeutic range
• Circadian phase dependent diseases

LINEAR PHARMACOKINETICS
Linear Pharmacokinetics:
• The linear pharmacokinetics is characterized by 1st order kinetics in distribution and elimination
kinetics of a drug.
• The same order of kinetics is assumed after increase of dose.
• For example, when the dose of a drug is doubled, the concentration in blood is doubled.

Graphical Representation:
• In linear pharmacokinetics, the graph is usually straight line on semi-log graph paper.
• In linear PK,
𝑨𝑼𝑪 ∝ 𝑫𝒐𝒔𝒆

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Characteristics:
• As we increase the dose, AUC will increase in proportional to it.
• Whether we draw the graph between lower concentration or higher concentration / Dose, the graph
will be straight line and the graph for higher concentration will be above the lower but in parallel form.
• Majority (95%) of the drugs follows the linear pharmacokinetics.
• In linear pharmacokinetics,
Only absorption parameters are dose dependent. The elimination parameters such as
clearance, half-life will not be affected.
• Plasma level time data follows 1st order kinetics.
• For example
o If we increase the dose from 60 mg/m2 to 90 mg/m2 i.e. dose is increased by 50%, then AUC
will also be increased by 50%
o We can also say that 100% increase in dose will increase AUC by 100%.
• AUC remains unchanged with change in dosing administration schedules i.e. AUC of doxorubicin
resulting from bolus dose of 60 mg/m2 equals AUC from 3 daily doses of 20 mg/m2 – Principal of
super position.

NON-LINEAR PHARMACOKINETICS
Introduction:
• The rate process of drug’s ADME are depend upon carrier or enzymes that are substrate specific, have
definite capacities and are susceptible to saturation at a high drug concentration.
• In such cases, an essentially first-order kinetics transform into a mixture of first-order and zero-order
rate processes and the pharmacokinetic parameters are changed with the size of the administered dose.
• Pharmacokinetics of such drugs are said to be dose dependent.
• Terms synonymous with it are mixed-order, nonlinear and capacity limited kinetics.

Why it is known as Mixed Order Kinetics?

• In some cases the kinetics of PK process changes from 1st order to zero order with increase in dose or
chronic medication.
• So mixture of both 1st and zero order observed in such cases.

Explanation:
• Being nonlinear means the effect of increase in one parameter results in disproportional increase,
decrease or no change in the other parameter.
• In pharmacokinetics, the area under the curve (AUC), an absorption parameter when plotted against
three graded doses (increased amounts) of drug it may proportionally increase, decrease or remains
unchanged.
• It is totally dependent on the dose given.
• Which means AUC is not directly proportional to the dose, rather it shows increased greater
proportions or increased lower proportions.
• When the levels of AUC increase not corresponding to dose, decrease or demonstrates no change with
increase in dose is called as the non-linear pharmacokinetics.
• Nonlinear pharmacokinetics is the deviations from the linear pharmacokinetic profile of a drug.
• Almost 5% drugs show non-linear behavior.
• Non-linearity leads to a higher or lower than the expected rise in concentration or AUC with increased
dose, as a result of dose-dependent changes in absorption, distribution and elimination process.

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 • Thus, the nonlinear kinetics is also known as capacity-saturation or saturation kinetics. In non-linear
pharmacokinetics, the kinetics of a process dealing with drug deviates from the first order kinetics,
which is the most commonly followed in pharmacokinetic processes.
• In terms of kinetics, this deviation is called as saturation kinetics, Michaelis-Menten of capacity-
limited kinetics.
When on At least one pharmacokinetic process (among absorption, distribution, metabolism or
excretion) does not follow the 1st order kinetics, the pharmacokinetics is called as non-linear
pharmacokinetics.

Example:
• AUC against 3 graded drug doses (increased amounts) may show increase, greater than proportional,
or increase lower than proportional. In non-linearity a higher or lower than expected (proportional)
rise in concentration or AUC with increased dose, as a result of dose-dependent changes in ADME
process.
• 5-FU shows 135% increase in AUC when its dose is increased by 100% i.e. from 7.5 – 15 mg/m2. It
shows increase above proportional.
• Paclitaxel AUC is higher, for some dose, but administered by shorter 3 hour versus 24 hr infusion
schedule.
• There are many other drugs such as paclitaxel, methotrexate etc. which show non-linear
pharmacokinetic behavior.
• In linear PK, elimination parameters were not changed but in non-linear pharmacokinetics, elimination
parameters are greatly affected that’s why AUC is seen not following proportionality with dose.

Detection of non-linearity in pharmacokinetics

There are several tests to detect non –linearity in pharmacokinetics but the simplest ones are:
• First test: Determination of steady state plasma concentration at different doses
• Second test: Determination of some important pharmacokinetic parameters such as fraction
bioavailability, elimination half-life or total systemic clearance at different doses of drug. Any change
in these parameters is indicative to non-linearity which are usually constant.

Graphical Representation:
• The graph for non-liner PK is not a straight line on semi-log graph paper.
• Initially it shows 1st order kinetics and later shows zero order kinetics. There are two compartments.
• The clearance and half-life is greatly affected in non-linear kinetics.

A few drugs are follows the nonlinear pharmacokinetics where an increase in dose causes a nonlinear
or disproportional change in blood concentration and thus, area under the curve (AUC).

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Conditions when drug follows non-linear pharmacokinetics:
• Plasma concentration time profile is not linear.
• AUC is not proportional to administered dose after administration of single dose.
• Steady state plasma concentration is not proportional to administered dose during multiple drug
administrations.
• Estimated PK parameters such as half- life and total body clearance are different after administration
of different doses.

Causes of Non-linearity:
A. Saturation of process
B. Saturation of transporter
C. Saturation of enzyme
D. Disproportional activation of endogenous entities, e.g., ATPase, P-pg
E. Pathologic conditions
F. Drug-induced

Effect of Saturation:
• There may be a greater saturation at enzyme’s substrate site or there may be greater saturation in GIT.
• The greater saturation will lead to non-proper absorption.
• ADME parameters are affected by increased dose
• There may be proportion metabolism of drug in GI wall.
• The slow clearance will promote greater half-life and Css will become hard to achieve.
• Drug reabsorption from kidney also occur at high doses.
• Examples of these saturable metabolic processes include glycine conjugation of salicylate, sulfate
conjugation of salicylamide, acetylation of p-aminobenzoic acid, and the elimination of phenytoin

Conclusion:
So these drugs should be monitored for their therapeutic doses. E.g. therapeutic dose of paclitaxel is
10 – 20 mg.
• At large doses the initial slow elimination is followed by a much rapid elimination a lower blood
concentration of blood.

Characteristics of Drugs following Saturation Kinetics:

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 1. Elimination of drug does not follow simple first-order kinetics— that is, elimination kinetics are
nonlinear.
2. The elimination half-life changes as dose is increased. Usually, the elimination half-life increases with
increased dose due to saturation of an enzyme system. However, the elimination half-life might
decrease due to “self”-induction of liver biotransformation enzymes, as is observed for carbamazepine.
3. The area under the curve (AUC) is not proportional to the amount of bioavailable drug.
4. The saturation of capacity-limited processes may be affected by other drugs that require the same
enzyme or carrier-mediated system (ie, competition effects).
5. The composition and/or ratio of the metabolites of a drug may be affected by a change in the dose.

Non-Linearity Occurs in:

• Drug Absorption
• Drug Distribution
• Drug metabolism
• Drug Excretion
1. Drug Absorption:
Three causes:
1. Solubility / dissolution of drug is rate-limited; Griseofulvin - at high concentration in intestine.
2. Carrier - mediated transport system; Ascorbic acid - saturation of transport system
3. Presystemic gut wall / hepatic metabolism attains saturation; Propranolol
• The parameters affected will be F, Ka, Cmax and AUC.
• A decrease in these parameters is observed in former two causes and an increase in latter cause.
2. Drug Distribution
At high doses non-linearity due to two causes:
1. Binding sites on plasma proteins get saturated; Phenylbutazone
2. Tissue binding sites get saturated
• In both cases there is increase in plasma drug concentration
• Increase in Vd only in (I)
3. Drug Metabolism
• Non-linearity occurs due to capacity limited metabolism, small changes in dose administration - large
variations in plasma concentration at steady state - large intersubject variability

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 • Two important causes:
o Capacity - limited metabolism - enzyme &/ cofactor saturation; Phenytoin, Alcohol
o Enzyme induction - decrease in plasma concentration; Carbamazepine.
4. Drug Excretion
Two active processes which are saturable:
1. Active tubular secretion - Penicillin G
2. Active tubular reabsorption - Water soluble vitamins & Glucose
• Saturation of carrier systems - decrease in renal clearance in case of I & increase in II. Half-life also
increases.
• Other reasons like forced diuresis, change in urine pH, nephrotoxicity & saturation of binding sites.

Examples of Drugs Showing Nonlinear Pharmacokinetics:

Causes Drugs
GI absorption
Saturable gastric or GI Decomposition Penicillin G, Saquinavir
Saturable transport in gut wall Riboflavin, Gebapentin, L-dopa, baclofen
Intestinal Metabolism Salicilamide, Propranolol
Low Solubility but high dose Chlorotiazide, griseofulvin, danazol
Distribution
Saturable transport into/ out of tissues MTX
Saturable plasma protein binding Phenylbutazone, lidocaine, salicylic acid
Cellular uptake Methicillin
Tissue binding IMI
CSF transport Benzylpenicillins
Metabolism
Saturable metabolism Phenytoin, salicylic acid, theophyllin, valproic acid
Enzymes induction Carbamazepine
Enzymes limitations PCT, alcohol
Altered hepatic blood flow Propranolol, verapamil
Metabolite inhibition Diazepam
Renal Excretion
Active secretion Mezlocillin, p-aminohippuric acid
Tubular reabsorption Riboflavin, ascorbic acid, cephapirin
Change in urine pH Salicylic acid, dextroamphetamine
Biliary Excretion
Biliary secretion Iodipamide, sulfobromophthalein sodium
Enterohepatic recycling Cimetidine, isotretinoin
Implications / Processes Involved in Non-linear Pharmacokinetics:
Nonlinear absorption results from saturation of carrier-mediated transport causing lower than
expected drug concentration with increase in dose. In absorption, the saturation of pre-systemic metabolism
in gut wall results in higher than the expected concentration since greater proportion of administered dose
survives the hepatic metabolism. For instance, higher doses of salicylates saturate its glycine conjugation in
children. There are three categories of drugs which affect P-gp differently. Category I drugs can stimulate P-
gp in low concentrations while inhibit P-gp at higher concentrations. On the other hand, category II drugs can
produce dose dependent activation of ATPase and class III can inhibit activity of ATPase. The category I can
lead to non-liner absorption/excretion/secretion due to the distribution of P-gp at relevant locations.
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 • Saturation of plasma protein binding causes nonlinear distribution and occurs when the drug
concentration exceeds binding capacity of protein, an effect is pronounced with the basic drugs that
bind to alpha-1 acid glycoprotein due to lower concentration of this protein than that of the albumin.
However, nonsteroidal anti-inflammatory drugs and valproic acid show nonlinear protein binding with
albumin.
• Saturation at tissue binding site will cause greater concentration in blood.
• Drugs saturating absorption or distribution are few and have no significant effect on clinical dosing.
• Saturation in portal system is also a reason of slow metabolism.
• Saturation of first pass metabolism in liver, respectively results in higher than the expected
concentration since greater proportion of administered dose survives metabolism. For instance, higher
doses of salicylates saturate its glycine conjugation in children.
• Nonlinear elimination occurs with saturation of renal or biliary secretion.
• Nonlinear elimination occurs for drugs undergoing hepatic metabolism and taken at higher but within
the clinical doses. Incremental dose of penicillin causes saturation of a transporter in renal secretion of
the drug leading to its non-linear elimination. Phenytoin saturates metabolism at upper range of clinical
dose while ethanol saturate even at lower dose.
So these drugs must be monitored for their therapeutic doses to avoid toxicity. Their half-life is affected
in such extent that a drug which is eliminated in 12 hours will then be eliminated in 1 to 3 weeks due to
saturation of drug. Their absorption is also shown at higher doses. And there may be several other reasons.

Indication of Non-Linear Pharmacokinetics:

In nonlinear elimination, rather than an exponential (first order) decline in the plasma concentration,
zero order elimination occurs initially shown by a straight line on the linear plot and convex curve on semi-
logarithmic graph. Until the concentration of drug falls sufficiently low, the elimination returns to first order
decline because the elimination process will no longer be saturated.

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Comparison of Michaelis-Menten Kinetics to Other Kinetics Orders:
The order of kinetics is determined by the graphical method and each order of kinetics gives a specific
profile when drawn as concentration against time and Ln-concentration against time (or on semi-logarithmic
graph paper). With linear concentration, the first order is a curved line (Figure 2 A), zero order kinetics shows
a straight line (Figure 2 C) and the Michaelis-Menten kinetic reflects a rapid decline and then a slow decline
due to saturation of the process (Figure 1 A). When the Ln-transformed concentration data is plotted on
ordinary graph (or the semi-logarithmic graph is used), the first order becomes a straight line (Figure 2 B) and
zero order gives an upward curve in Figure 2 C. For the Michaelis-Menten kinetics, the line with Ln-
transformed concentration yields a slow and then a fast decline (Figure 1 B). The profile in graph (Figure 1 B
deviates from linearity (zero order) and then becomes linear (first order).

Interpretation:
In first order kinetics the rate of decline of drug concentration depends on the concentration. In zero-
order kinetics, the decline is independent of the drug concentration in the tissue. Michaelis-Menten kinetics is
usually applicable to drug elimination where the drug elimination depends on the degree of saturation of the
elimination process. In this kinetics, the enzyme involved in drug biotransformation is activated in a manner
dependent on the drug concentration.

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Michaelis Menten Equation:
Nonlinear pharmacokinetics can be best described by Michaelis Menten Equation.
𝑑𝑐 𝑉𝑚𝑎𝑥 𝐶
− =
𝑑𝑡 𝐾𝑚 + 𝐶
Where,
• -dC/dt = rate of decline of drug conc. with time
• Vmax = Theoretical max. rate of process
• Km = Michaelis constant
When Km = C When Km>>C When Km<<C
𝑑𝑐 𝑉𝑚𝑎𝑥 𝑑𝑐 𝑉𝑚𝑎𝑥 𝐶 𝑑𝑐
− = − = − = 𝑉𝑚𝑎𝑥
𝑑𝑡 2 𝑑𝑡 𝐾𝑚 𝑑𝑡

Impact of Non-linearity on Pharmacokinetics:

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 Due to this complex kinetics, the equations used for linear pharmacokinetics are not applicable, though
the concept of compartment model is still applicable. Application of linear pharmacokinetic models to drug
showing nonlinear pharmacokinetics may lead to large or frequent dosing leading to an unexpected
accumulation of drug. Nonlinear pharmacokinetic models require the application of more complicated,
enzyme or saturation (Michaelis-Menten) kinetic theory, thus non-linear kinetics is also called as Michaelis-
Menten kinetics.

Parameters of Nonlinear Pharmacokinetics:

It is clinically important to know the dose causing saturation of process to avoid drug accumulation
and toxicity. Knowledge of the maximal rate of elimination (Vmax) is important. The Km is the concentration
at the half maximal rate of elimination.
The rate constant rate constant of decline, Vmax is calculated using equation for slope (m) from the top
left straight line on the linear graph by using the equation:
𝑉𝑚𝑎𝑥 = – 𝑚
The C0 (y-intercept) is estimated from the straight line at the top left of the semi-logarithmic graph.
The Kel is calculated from the linear terminal slope of the curve on semi-logarithmic graph. The half-life is
calculated as:
0.693
𝑡1/2 =
𝐾𝑒𝑙
The Km and Vd are calculated using the equations:
𝑉𝑚𝑎𝑥
𝐾𝑚 =
𝐾𝑒𝑙
𝐷𝑜𝑠𝑒
𝑉𝑑 =
𝐶0

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