GUAYAQUIL UNIVERSITY

FACULTY OF CHEMICAL SCIENCES

BIOPHARMACY

ISSUE:
LINEAR AND NON-LINEAR KINETICS:
ABSORPTION, DISTRIBUTION AND
ELIMINATION. MULTIPLE DOSE KINETICS.

MEMBERS
 BERRÚS JIMÉNEZ HELEN
 ELIAS OLIVO MICHELLE
 LOOR MOREIRA EMANUEL
 RENDON PLUAS LADY
 SEGARRA RODRÍGUEZ JOSELYN

GROUP 3 – TEAM 8

CYCLE II: 2018 – 2019

INDEX
INTRODUCTION...................................................................................................................3
PHARMACOKINETICS........................................................................................................3
LINEAR PHARMACOKINETICS..........................................................................................4
LINEAR KINETICS...............................................................................................................5
EXAMPLE 1 OF LINEAR PHARMACOKINETICS.................................................................................5
EXAMPLE 2.....................................................................................................................................6
EXAMPLE 3.....................................................................................................................................6
NON-LINEAR PHARMACOKINETICS.................................................................................7
NON-LINEAR KINETICS (ZERO ORDER)............................................................................................9
Identification of nonlinear kinetics.................................................................................................9
Superposition principle..................................................................................................................9
CAUSES OF NONLINEAR KINETICS..................................................................................................9
Absorption..................................................................................................................................9
Distribution................................................................................................................................9
Renal or Biliary Excretion...........................................................................................................9
Metabolism..............................................................................................................................10
Differences between linear and non-linear pharmacokinetics.....................................................11
ELIMINATION KINETICS................................................................................................................11
MULTIPLE DOSE KINETICS.............................................................................................13
Multiple intravascular and extravascular doses...........................................................................14
Multiple intravascular doses........................................................................................................15
Extravascular multiple doses........................................................................................................16
Multiple doses with initial dose....................................................................................................17
Balance of distribution (Multiple Doses)......................................................................................18
BIBLIOGRAPHY.................................................................................................................18
 INTRODUCTION

Linear processes are also called independent doses or independent concentration, here
we find the absorption, distribution and elimination processes that are of order 1.

Pharmacokinetic parameters such as half-life, clearance, volume of distribution are

constant, they do not depend on the concentration of active ingredient in the body,
changes in the dose produce proportional changes in drug concentrations.

On the other hand, nonlinear processes are also called dose-dependent or concentration-
dependent, at least one of the kinetic processes such as absorption, distribution or
elimination is saturable.

In these processes, the pharmacokinetic parameters such as half-life, clearance, volume

of distribution are not constant, they are concentration dependent and changes in the dose
do not cause proportional changes in the concentrations. drug ones.

In multiple dose kinetics, the objective of administering a drug in multiple doses is the
same as that of administration by intravenous infusion: to achieve a level of drug in the
body and maintain it for a time so that it exerts its therapeutic effect. In other words:
achieving effective levels in the body capable of exerting the desired therapeutic action.

PHARMACOKINETICS

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Pharmacokinetics studies the time course of drug concentrations in the body and builds
models to interpret these data and therefore to assess or predict the therapeutic or toxic
action of a drug.

LINEAR PHARMACOKINETICS

It is the branch of pharmacokinetics that studies processes that are distinguished by first-
order kinetics. One of the characteristics of linear pharmacokinetics is manifested in the
relationship of direct proportionality between the magnitude of the administered doses and
the plasma concentrations of the drug, or between the respective areas under the curve.

Also called independent doses or independent concentration, the processes of absorption,

distribution and elimination are of order 1.

Linear pharmacokinetics has order 1, so that the rate is proportional to the drug
concentration at the site of origin (behavior). The speed of the process is proportional to
the concentration (C0) at that moment. The half-life does not depend on C0.

The passive processes follow this kinetics:

 Passive release: This strategy is very interesting in parenteral administration
(intramuscular and subcutaneous) to reduce the number of punctures. The most
prominent example is the coupling of insulin with zinc and mechanical pencils to create
insulins that have to be administered fewer times a day.
 Passive absorption: The drug simply collides with the cell membrane and manages to
pass through it. It is the majority form of substance absorption.
 Distribution aqueous sectors.
 Glomerular filtration.
 Passive tubular reabsorption.
 Passive diffusion in bile.

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LINEAR KINETICS

A linear pharmacokinetic model is one whose kinetic processes correspond to 1st order
kinetics. In this case: The area under the curve (AUC) of plasma concentration versus time
is proportional to the dose administered.

The elimination rate is proportional at each moment to the amount of drug or toxicant
available to be eliminated.

EXAMPLE 1 OF LINEAR PHARMACOKINETICS

As reported by Gu et al., (2014) in their study on Determination of liquiritigenin by liquid

chromatography applied to a linear pharmacokinetic study in rats, it meets the following
conditions:

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 Table I. Conditions and considerations for liquiritigenin testing in rats
RATS MALE
Weight 250 to 300g
Housing temperature 20 + or – 5 °C
RH 30 – 70% for 12 hours
Light Cycle Darkness
You fast 12 hours
Access to water before starting the experiment

Liquiritigenin was dissolved with 40% propylene glycol (prepared with water for injection),
yielding concentrations of 0.5, 1.2 mg/ml. The rats were divided into three groups of low,
medium and high concentration, administered intravenously at 0.5, 1 and 2 mg/kg,
respectively, through the tail vein after ether anesthesia (n = 6). The administration time
was calculated by the effective dose from our previous study in mice, which indicated that
20 mg/kg could be the optimal dose for inhibitory effects. 0.3 ml venous blood samples
were collected for different time points at zero (control), 1 (end of infusion), 3, 5, 7, 10, 20,
30, 45, 60, 180, 360 minutes after the start of intravenous administration. .

Blood samples were placed in heparinized tubes and immediately centrifuged at 12,000
rpm for 5 minutes at 4 °C to collect plasma. The plasma samples obtained were stored at
−20°C until analysis.

EXAMPLE 2

The plasma concentration of valproic acid is calculated in a patient with status epilepticus.
Cp= 30 μg/mL Therapeutic range: 50-100 μg/mL.

Since it is below the minimum effective concentration, we would have to double the dose
to double the plasma concentration and make it within the therapeutic range.

EXAMPLE 3

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The plasma concentration of phenytoin is calculated in a patient with status epilepticus.
Cp= 7 μg/mL Therapeutic range: 10-20 μg/mL.

By increasing the dose, there is a saturation of the enzymatic system that metabolizes
PHENYTOIN, therefore if we double the dose the plasma concentration will more than
double.

NON-LINEAR PHARMACOKINETICS

The kinetics of absorption, distribution, biotransformation and excretion processes are not
first order. A characteristic of nonlinear pharmacokinetics is the lack of direct
proportionality between changes in administered doses and plasma drug concentrations or
their areas under the curve.

In the case of dose-dependent kinetics for each drug concentration, it is related to the
slope of the tangent to the curve at the corresponding point. It can be seen in Figure 1 that
this slope decreases as the kinetics approaches order 0, that is, the half-life increases.
This is what is generally observed with drugs with dose-dependent kinetics: the half-life is
prolonged with increasing dose. For example, if 325 mg of aspirin are administered, the
half-life of salicylic acid is approximately 2 h, if 1 g of aspirin is administered, the half-life is
close to 4 h, and in poisonings, half-lives close to 8 p.m. Most drugs have more than one
elimination mechanism, and not all are saturated with the same concentration of drug. This

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implies that, when one elimination mechanism has been saturated, the others continue to
eliminate the drug with kinetics of order 1.

Figure 1. Dose-independent and dose-dependent kinetics

This is because one of the kinetic processes that the drug undergoes in the body adjusts
to more complex kinetics than the first order.
These processes involve enzyme systems or transporters that are specific in terms of the
substrate and finite in terms of their capacity, which can lead to their saturation at the drug
concentrations that are reached in the body.
Metabolism or biotransformation and active tubular secretion are the kinetic processes that
frequently become saturated, especially in overdose situations.
Due to these saturable kinetic processes, the relationship between 〖𝐴𝐵𝐶〗 _0^∞ or ¯ 𝐶 𝑠𝑠
and dose is not linear.
This phenomenon is of clinical interest, when it occurs at usual therapeutic doses.

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NON-LINEAR KINETICS (ZERO ORDER)

In this type of kinetics, the elimination rate is independent of the amount of drug present in
the body. This phenomenon is explained by the saturation of the biological systems
responsible for eliminating the drug from the body. In this case, the amount of drug that is
eliminated per time interval is constant and its value is defined by the maximum capacity of
the elimination systems.

Identification of nonlinear kinetics

The estimated pharmacokinetic parameters, such as half-life or clearance, are different
when different doses are administered.

Superposition principle
The plasma concentration and the amount of drug and its metabolites excreted in the
urine, at any given time, increase in direct proportion to the increase in dose, whether
single or multiple. Correcting for the dose, the values overlap at all times.
Usually in plasma, the amount of drug and metabolites excreted in urine increase
proportionally with the dose. By normalizing the curves (Cp/Dose) → Overlay.
CAUSES OF NONLINEAR KINETICS

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Absorption
 Saturation of the active transport system at the intestinal level
 Low solubility of the drug.
 Modification of intestinal blood flow that causes a modification in the rate of absorption.
 Saturation of the intestinal or hepatic enzyme system responsible for the first pass
effect.

Distribution
 Plasma protein binding saturation.
 Saturation of fixation at the tissue level.
 Saturation of a transportation system.

Renal or Biliary Excretion

 Saturation of the active secretion system at the level of the renal tubules.
 Saturation of active tubular reabsorption.
 Saturation of binding to plasma proteins with the consequent increase in
glomerular filtration.
 Modification of urinary pH due to increased drug concentration.
 Modification of urine volume due to dose effect.
 Saturation of biliary excretion.

Metabolism
 Saturation of enzyme systems with increasing dose.
 Enzymatic autoinduction over time.
 Enzymatic inhibition due to a product of metabolism.
 Modification of hepatic blood flow.
 Saturation of plasma protein binding with effect on metabolism.

 The most important cause of nonlinear or dose-dependent kinetics is the saturation

of this process. The saturation of the enzymatic systems responsible for
biotransformation, the speed of elimination through this route is no longer directly

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 proportional to the concentrations reached in the organism, losing first-order kinetic
behavior. The next Equation describes the process:
−d C t V M .C t
o =
dt K M + Ct

 MV = maximum rate of biotransformation of the drug in the body (depends on the

cc of enzymes available for metabolization), KM = Michaelis-Menten constant
(inversely related to the affinity of the drug for the enzyme).

 MV is expressed in units of elimination rate, amount/time (mg/day) or [(mg/L)/h]

Differences between linear and non-linear pharmacokinetics

LINEAR PHARMACOKINETICS NON-LINEAR PHARMACOKINETICS

• Independent dose • Dose dependent

• Dose changes cause proportional • Changes in dose do not cause
changes in the Cp of the drug proportional changes in the C p of
• Absorption, distribution and the drug
elimination follow first-order • At least one of the ADME
kinetics processes is saturable.
• The pharmacokinetic parameters t • The pharmacokinetic parameters t
1/2, CL t , V d are constant and 1/2 , CL t , V d are dependent on the
independent of the C p of the drug C p of the drug.

ELIMINATION KINETICS

The elimination constant expresses the probability that a molecule has to be eliminated in
the unit of time. The elimination half-life is the time it takes for the plasma concentration of

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a drug to be reduced by half. This value is related to the elimination constant and is of
great importance in deciding the administration schedule. The disposition constant β is the
most important for predicting the time course of plasma levels in the two-compartment
model.

Most elimination mechanisms are of order one and the rate of elimination is greater when
plasma concentrations of the drug are high. If the removal mechanism is saturated, the
number of molecules removed will remain constant. The process then adjusts to zero-
order kinetics.
However, saturable processes usually conform to mixed-order kinetics and are governed
by the Michaelis Menten equation. The kinetics of a drug is linear when its absorption,
distribution and elimination constants do not vary with time and do not vary when the dose
is modified. The mechanisms for nonlinearity generally affect elimination.

In pharmacokinetics, rate is expressed in units of mass (μg, mg, etc.) per unit of time (min,
h, etc.). There are two types of elimination kinetics, linear kinetics (order one) and
nonlinear kinetics (order zero).

Elimination, absorption, protein binding, distribution, etc., can each be dose dependent or
dose independent. The area under the curve between zero and infinite times (AUC) is
used to determine whether or not all kinetics of a drug are dose independent. The analysis
of the concentration-time curves corresponding to various doses of the same drug is
carried out and, then, the areas under the curve are represented as a function of the dose.
If a straight line is obtained, the drug has linear kinetics (dose independent). .

The kinetics of a drug is linear when its absorption, distribution and elimination constants
do not vary with time and do not vary when the dose is modified. In this case, there is a
linear relationship between doses administered and stable levels achieved, with the time it
takes to reach the stable level remaining constant. On the contrary, a drug is said to have
non-linear kinetics when its absorption, distribution or elimination constants vary with time
or dose. The mechanisms for nonlinearity can affect any of the absorption, distribution, or
elimination processes, but generally, nonlinear kinetics are due to saturation of protein
binding, hepatic metabolism, or active renal transport of the drug and affect its elimination.

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The dose-dependent elimination kinetics can be increasing or decreasing. In the first case,
the level increases more than corresponds to the dose; This is what happens when the
diphenylhydantoin or salicylate metabolizing system is saturated. In dose-dependent
elimination kinetics of the decreasing type, the level increases less than corresponds to
the dose; This is what occurs due to the saturation of the binding of valproate to plasma
proteins. The main consequences of protein binding saturation are the opposite of those of
protein binding saturation are the opposite of those of metabolism saturation.

When both coexist, their respective effects can practically cancel each other out and
surprisingly linear kinetics can appear. This happens, for example, within certain
concentration limits; for salicylic acid, there may also be time-dependent kinetics; this is
the case of carbamazepine, whose metabolism is subject to autoinduction phenomena. In
this case, the half-life after the first dose is twice that observed in the stable phase. When
there is time-dependent kinetics due to a phenomenon of autoinduction in metabolism, the
result, in a way, is also opposite to that observed with saturation of the metabolization
mechanisms.

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MULTIPLE DOSE KINETICS

Pharmacokinetic models allow estimating the plasma concentration that will be reached in
a certain time and the time in which a certain plasma concentration will be reached. They
are also used to calculate the maximum concentration that is expected to be achieved
after an initial dose, the stable level that will be reached with a maintenance dose and, vice
versa, the dose that must be administered to achieve a certain plasma concentration.

When multiple doses are administered, this makes it possible to estimate the fluctuation in
plasma concentration that will be observed with an administration interval and, vice versa,
the interval that must be used to avoid excessive fluctuation. If the pharmacokinetic
constants of a specific patient are not known, the population constants are initially applied,
that is, the average constants obtained in a population with characteristics similar to those
of the patient.

Abbreviations

 D = Dose administered
 t = Time
 Q = Continuous intravenous infusion rate.
 Cmax = Maximum plasma concentration.
 CmaxE = Maximum plasma concentration at equilibrium.
 CminE = Minimum equilibrium plasma concentration. Cp = Plasma concentration of
the drug.
 f = Bioavailable absorption fraction.
 CpE = Plasma concentration at equilibrium or average stable level.
 DM = Maintenance dose
 DI = Initial dose .
 MCE = Minimum effective concentration.
 CMT = Minimum toxic concentration
 t1/2e = Elimination half-life
 Ka = Absorption constant.
 KD = Equilibrium dissociation constant.
 Ke = Elimination constant

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Multiple intravascular and extravascular doses

It is the most widely used way to establish and maintain chronic treatment. The difference
between repeated single doses and multiple doses depends on the interval between
doses: when it is greater than 5 half-lives, the entire previous dose will have been
eliminated and the time course of the plasma concentration will be the same as that of the
first dose. However, when it is less than 5 half-lives, the new dose is added to what
remains of the previous one, producing an accumulation that increases the plasma
concentration (fig. 2).

Fig. 2. Time course of the plasma

concentration of a drug when
repeated doses of the drug are
administered separated by an
interval greater than 5 half-lives
(A) or less than 5 half-lives (B).
The area under the curve after
the first dose (a) is equal to the
area under the curve after any
dose in the steady-state phase
(b).

When treatment with multiple doses is instituted without an initial dose, the time course of
levels is similar to that described for continuous intravenous infusion since, as in this case,
a fixed amount (D) is administered at an administration interval ( t), so that the D/t ratio is
equivalent to the infusion rate (Q). The plasma concentration increases rapidly at first and
more slowly thereafter, until the input equals the output, at which time the plasma
concentration will remain constant for the duration of treatment.

The main difference with continuous infusion is that, after each dose, there is a fluctuation
in plasma concentration throughout the administration interval, with a maximum (CmaxE)
and a minimum (CminE), that is, with a fluctuation (f ') which can be expressed as:

15
The slower the elimination of the drug, the greater the accumulation factor (R), that is, the
relationship between the concentration reached in the steady-state phase and that
observed after the first dose (Fig. 1).

The objective of this dosing schedule is to use a dose and interval that maintains the
maximum stable concentration below the minimum toxic concentration and the minimum
stable concentration above the minimum effective concentration (Fig. 1).

Multiple intravascular doses

By intravenous route, the absorption fraction is considered to be 1 and, therefore, the

mean stable level (CpE), equivalent to that of continuous infusion, depends on the
maintenance dose (MD/t) and drug clearance.

 That is, it depends directly on the maintenance dose and inversely on clearance.
 The time it takes to reach the stable level depends exclusively on the elimination
constant.
 The fluctuation of plasma concentration (f') depends exclusively on the elimination
constant and the administration interval.

That is, if we need to reduce the fluctuation, drugs with a long half-life should be used or
the administration interval should be shortened. The shortening of the interval without
changing the D/t ratio (p. (e.g., going from 450 mg theophylline every 12 hours to 300 mg
every 8 hours) reduces the fluctuation without changing the stable level. A general rule of
thumb to avoid excessive fluctuation in plasma concentration is to use a dosing interval
similar to the elimination half-life of the drug, which will result in a 50% fluctuation.

The use of intervals greater than the half-life will produce excessive fluctuation, only
tolerable with drugs with a large therapeutic index, while the use of an interval less than
the half-life reduces the fluctuation, improving tolerability.

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Hence, in chronic treatments, it is considered advisable to use drugs with a half-life greater
than 12 hours that allow the number of doses per day to be reduced to one or two. With
drugs that have a shorter half-life it is advisable to use a sustained release preparation

Extravascular multiple doses

When administration is extravascular, the absorption fraction may be less than one. On the
other hand, the time it takes to reach the stable level depends not only on the elimination
constant but also on the absorption constant.

When absorption is rapid (more than 10 times greater than elimination) the stable level is
still considered to be reached in 5 half-lives but, when it is slow, it lengthens the time it
takes to reach the stable level with respect to intravenous administration.

The fluctuation of plasma concentration during an administration interval will also depend
on the absorption constant, being less with respect to intravascular administration the
slower the absorption.

Fig 3. Multiple extravascular doses with and

without initial dose. Note the influence of the
initial dose/maintenance dose (ID/MD) ratio
when the administration interval is equal to
an elimination half-life .

Multiple doses with initial dose

An initial dose can be administered either intravascularly or extravascularly to achieve a

therapeutic concentration more quickly. As a general rule, when the maintenance dose is

17
administered with an interval equal to one elimination half-life, an initial dose twice that of
the maintenance dose is needed to achieve a maximum initial concentration equivalent to
the stable level (Fig. 3).

When the interval is less than the half-life, an initial dose greater than the maintenance
dose is required (e.g. e.g., for digoxin), while when the interval is longer, the initial dose is
similar to the maintenance dose and it is usually not necessary to administer an initial dose
(e.g. e.g., with aminoglycosides) (Table 2).

If the patient was already receiving the drug, the initial dose will be added to the
preexisting level, so the initial dose should be lower. When drugs with a small therapeutic
index are used, in less urgent situations, it is preferable to avoid initial doses as they may
be accompanied by side effects. It is even usually advisable to start treatment with lower
doses than usual and increase them gradually.

Table 2. Relationship between the initial dose and the maintenance dose for different
administration intervals in the one-compartment model

Balance of distribution (Multiple Doses).

Distribution equilibrium is a state to which the drug will tend in the body, but which will only
be genuinely approached in the case of using a delivery system that delivers the drug in a
continuous and constant manner. By other routes and forms of administration, the steady

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state will be reached after administering multiple and identical doses at regular intervals. In
these cases, the steady state will be defined by the periodic fluctuation of plasma drug
levels between practically constant maximum and minimum plasma concentrations. It is
therefore a pseudo-steady state, in which plasma concentrations will oscillate within an
approximately fixed range of plasma levels.

Figure 4. Plasma concentration versus time for a drug that is administered rapidly intravenously in
multiple doses.

BIBLIOGRAPHY

 Armijo, J. TO. (1997). Drug administration guidelines. Jesus Florez. Human

pharmacology. 3a. edition. Masson Publishing. Barcelona, 87-105.

 Fernández, P. L. (2015). Farmacocinetica Lineal y No lineal. En Farmacología Básica

y Clínica (págs. 147-158). Madrid: Ed. Médica Panamericana.

 Rothlin, R., & Tessler, J. (2007). Cinetica de acumulación Cinética de eliminación

Principios Generales.Mexico: Adventure.

 Cutler, D. J. (1978). Linear systems analysis in pharmacokinetics. Journal of

Pharmacokinetics and Biopharmaceutics, 6(3), 265–282. doi:10.1007/bf01312266

 Harris, D. (2004). Clinical Pharmacokinetics. Obtenido de

https://ocw.ehu.eus/pluginfile.php/1190/mod_resource/content/1/Temas/
Tema_14._Cinetica_no_lineal_OCW.pdf

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 Gu, J., Li, H., Pei, K., Cai, H., Qin, K., Zhang, X., Cai, B. (2014). Determination of
liquiritigenin by ultra high performance liquid chromatography coupled with triple
quadrupole mass spectrometry: Application to a linear pharmacokinetic study of
liquiritigenin in rat plasma. Journal of Chromatography B, 973, 120–125.
doi:10.1016/j.jchromb.2014.09.002

 Brocks D, M. R. (2010). los Parámetros Farmacocinéticos Vinculados con la

Acumulación de Medicamentos.

 Cinética De Eliminación De Los Fármacos. (2009).

 Harris, D. (2004). Clinical Pharmacokinetics. Obtenido de

https://ocw.ehu.eus/pluginfile.php/1190/mod_resource/content/1/Temas/
Tema_14._Cinetica_no_lineal_OCW.pdf

 Nella, D. M. (2007). Farmacocinética no lineal.

 Universidad Alcala. (2011). Obtenido de

https://portal.uah.es/portal/page/portal/GP_EPD/PG-MA-ASIG/PG-ASIG-31955/
TAB42351/T21-PK%20NO%20LINEAL-2008.pdf

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