Part 8. QUANTITATIVE PHARMACOKINETICS
THE KINETICS OF DRUG ELIMINATION
A. THE KINETICS OF DRUG ELIMINATION
I. INTRODUCTION
II. FIRST-order elimination (concentration-dependent elimination) features
III. ZERO-order elimination (capacity-limited elimination) features
IV. What determines the elimination kinetics of a drug?
The mechanism of elimination:
if conc-dependent: 1st-order (diffusion, filtration, transport or biotr at conc <KM)
if capacity-limited: 0-order (transport or biotransformation at concentration >KM;
or limited cosubstrate supply)
V. Change in elimination kinetics from first- to zero-order
B. PHARMACOKINETIC ANALYSIS OF THE PLASMA
CONCENTRATION versus TIME CURVE (PCvsTC)
I. Analysis of first-order drug elimination ONE-COMPARTMENT MODEL,
INTRAVENOUS ADMINISTRATION: C 0, Vd, T1/2, Cl
II. Analysis of first-order drug elimination ONE-COMPARTMENT MODEL,
ORAL ADMINISTRATION
III. Analysis of first-order drug elimination ONE-COMPARTMENT MODEL,
REPEATED DRUG ADMINISTRATION
1. The steady state
a. Time to steady state: 4-5 T1/2
b. Css is directly related to DR, and is inversely related to Cl
c. Cmax-Cmin is directly related to dosing interval (T) and is inversely related to T1/2
2. Pharmacokinetic objectives of repeated dosing
a. To establish Css in the therapeutic window
b. To establish therapeutic Css within a reasonable time for drugs with long T1/2, give
Loading dose (DL = Css Vd) first, and then
Maintenance dose (DR = Css Cl)
IV. Analysis of first-order drug elimination TWO-COMPARTMENT MODEL,
INTRAVENOUS ADMINISTRATION
C. APPENDIX
I. Interpretation of pharmacokinetic parameters of some drugs Examples
II. Calculation of hemodialysis and hemoperfusion clearances of drugs
III. Where do 0.693 and 2.3 come from in equations T1/2 = 0.693 : Kel and
Kel = -slope 2.3, respectively?
IV. Another way to plot the PCvsTC: Plotting the lg concentrations in a normal graph
rather than the concentrations in a semilog graph get C0 and the slope easily
NOTES: 1. Sections A, B-I, and B-III are especially important to understand! 2. The concept of
clearance (Cl) is easy to understand if you consider the pot-and-dipper figure (see inside).
Alternatively, you could call it a bean soup or pea soup figure.
A.
I. INTRODUCTION
Pharmacokinetic analysis deals with the mathematical description of
absorption,
distribution, and
elimination of drugs.
Here the focus is placed on the mathematical description of elimination, as that is
most useful for a clinician. For example, calculation of the clearance, an important
descriptor of the elimination of a drug, allows the clinician to determine the dose rate of
the drug that is needed to reach therapeutic concentration in the plasma.
Elimination (which includes excretion and biotransformation) is solely responsible for
the decline of the concentration of the drug in blood plasma following distribution.
Therefore, elimination of drugs can be mathematically described by analyzing the
plasma concentration versus time curve (PCvsTC), i.e. the curve that depicts the
disappearance of the drug from the plasma.
Disappearance of drugs from the blood plasma may follow two types of kinetics:
First-order kinetics called first-order because the change in plasma concentration
(c) in time (t), i.e. the rate of elimination, is described by the following equation (where
k is the rate constant):
c/t = -k c1 = -k c That is: the rate of elimination is concentration-dependent.
First-order kinetics characterizes the elimination of most drugs (when given in the
therapeutic dose range).
Zero-order kinetics called 0-order because the change in plasma concentration
(c) in time (t), i.e. the rate of elimination, is described by the following equation:
c/t = -k c0 = -k That is: the rate of elimination is concentration-independent.
Zero-order kinetics characterizes the elimination of a few drugs (when given in the
therapeutic dose range, however, it is not uncommon in drug overdose).
Because zero-order elimination is uncommon for drugs given in therapeutic doses, quantitative
analysis of drug elimination will be restricted to analysis of the elimination of drugs that follow first-
order kinetics. Nevertheless, the features and mechanisms of zero-order elimination as well as the
phenomenon of first- to zero-order conversion of drug elimination kinetics are important to consider
and will be discussed.
The shape of the plasma concentration versus time curve (PCvsTC) usually
reveals whether the elimination kinetics of a drug is of first order or zero order.
The shape of the PCvsTC depends on how we plot the plasma concentration values in
a graph, i.e. whether we plot them in a graph whose Y axis has an arithmetic scale
or a logarithmic scale see the following two pages.
II. FIRST-order elimination
in a graph whose Y axis has an arithmetic scale, FIRST-order elimination appears
as a monoexponential decline = a concave line (figure, top left); whereas
in a graph whose Y axis has a logarithmic scale, FIRST-order elimination appears
as a linear decline = a straight line (figure, bottom left).
The features of FIRST-order elimination can be deduced from the PCvsTC:
1. The absolute decline in plasma concentration is concentration-dependent,
and it is directly related to the plasma concentration:
Large decline at high concentration (i.e. early after dosing)
Small decline at low concentration (i.e. later after dosing)
See the absolute declines in the figure (top left):
1st hr: 50 mg/L, 2nd hr: 25 mg/L, 3rd hr: 12.5 mg/L.
Implication: The rate of elimination is concentration-dependent, i.e. it is directly
proportional to the concentration of the drug.
2. The fractional decline in plasma concentration is steady (constant),
and is concentration-independent.
See the fractional declines in the figure (top left):
1st hr: 50%, 2nd hr: 50%, 3rd hr: 50%.
Implication: The same fraction of the dose is eliminated in each unit of time.
IN SUMMARY: FIRST-order elimination is conc-dependent elimination. Therefore,
decreasing absolute amounts of the drug, but the same fraction of the dose in the body
(body burden) is eliminated in each unit of time as time passes after dosing.
III. ZERO-order elimination
in a graph whose Y axis has an arithmetic scale, ZERO-order elimination appears
as a straight line (figure, top right) ); whereas
in a graph whose Y axis has a logarithmic scale, ZERO-order elimination appears
as a convex line (figure, bottom right).
The features of ZERO-order elimination can be deduced from the PCvsTC:
1. The absolute decline in plasma concentration is steady (constant),
and it is independent of the concentration.
See the absolute declines in the figure (top right):
1st hr: 10 mg/L, 2nd hr: 10 mg/L, 3rd hr: 10 mg/L.
Implication: The rate of elimination is steady (constant), i.e. concentration
independent: the same amount of drug is eliminated at each unit of time.
2. The fractional decline in plasma concentration is concentration-dependent
and is inversely related to the plasma concentration.
See the fractional declines in the figure (top right):
1st hr: 10% (from 100 to 90 g/mL), 6th hr: 20% (from 50 to 40 g/mL).
Implication: Increasingly larger fractions of the dose of the drug are eliminated
with the passage of time after drug administration.
IN SUMMARY: ZERO-order elimination is a concentration-independent, capacity-
limited elimination. Therefore, the same absolute amount of the drug is eliminated in
each unit of time, which represents larger and larger fractions of the dose in the body
(body burden) as time passes after dosing.
IV. What determines the elimination kinetics of a drug?
The elimination kinetics depends on the MECHANISM of drug elimination:
If the elimination mechanism is CONCENTRATION-DEPENDENT,
then the elimination of the drug follows FIRST-order kinetics.
If the elimination mechanism is CAPACITY-LIMITED (concentration-independent),
then the elimination of the drug follows ZERO-order kinetics.
CONSIDER three possible cases: 1, 2a, 2b:
1. For drugs eliminated only by diffusion or filtration (which are concentration-
dependent processes), the elimination must follow FIRST-order kinetics. Examples:
N2O (nitrous oxide) is eliminated by exhalation (i.e. diffusion across the alveolar
cells), which is a concentration-driven process FIRST-order elimination
Aminoglycoside antibiotics are eliminated by glomerular filtration, the rate of which
is dependent on the plasma concentration FIRST-order elimination
2. For drugs eliminated by
excretion via carrier-mediated transport (tubular secretion, biliary excretion), or
enzyme-catalyzed biotransformation, the elimination kinetics depends on
the concentration of the drug in the vicinity of the transporter or the enzyme:
a. If the drug conc is at or below the KM, FIRST-order elimination should occur,
because in that conc-range the transport rate or the metabolite formation rate
is concentration-dependent (see the figure below).
b. If the drug conc is higher than the KM and is near or above the saturating
concentration, ZERO-order elimination should occur, because at saturating
conc the transport rate or the metabolite formation rate is steady (constant), i.e.
concentration-independent and capacity-limited (see the figure below).
Ad 2a. Examples for drugs whose elimination is carrier- or enzyme-mediated, yet is
conc-dependent in therapeutic doses, therefore it follows FIRST-order kinetics:
Penicillin:
Elimination mechanism: tubular secretion by OAT1 MRP4 or OAT4 transporters.
OAT1 has high capacity (3 M units/hr/person), low affinity (high KM ).
The usual dose of penicillin (1 M units/day); the concentration does not saturate OAT1
Concentration-dependent, FIRST-order elimination
Lidocaine:
Elimination mechanism: N-deethylation by CYP1A2 and (at higher conc) by CYP3A4.
CYP3A4 is abundant in human liver + it has high capacity, low affinity (high KM).
The therapeutic dose (conc) of lidocaine, does not exceed its Km for CYP3A4
Concentration-dependent, FIRST-order elimination
Ad 2b. Examples for drugs whose elimination are enzyme-mediated and are conc-
independent = capacity limited at average or high therapeutic doses,
therefore their elimination follows ZERO-order kinetics:
Phenytoin:
Elimination mechanism: 4-hydroxylation by CYP2C9
- CYP2C9 is present in low amounts in human liver,
- the KM of phenytoin for CYP2C9 is ~6 mg/L;
- the therapeutic concentration of phenytoin is 10-20 mg/L.
If the dose of phenytoin is 300 mg, its concentration is 15 mg/L (i.e. >KM), therefore
CYP2C9 becomes saturated by >300 mg phenytoin:
the metabolite formation rate becomes limited by the capacity of CYP2C9.
Capacity-limited, concentration-independent, ZERO-order elimination
Salicylic acid (the immediate metabolite of aspirin):
Elimination mechanism: conjugation with glycine salicyl-glycine (salicyluric acid)
Glycine availability does not limit the capacity of conjugation at low therapeutic dose of
aspirin (0.5 g), however, at aspirin dose >2 g glycine supply becomes rate-limiting.
Capacity-limited, concentration-independent, ZERO-order elimination
Ethanol:
Elimination mechanism: dehydrogenation by alcohol dehydrogenase using NAD+
- NAD+ availability limits the capacity alcohol dehydrogenation
- NAD+ availability is limited by the capacity of reoxidation of NADH to NAD+
capacity-limited, concentration-independent, ZERO-order elimination
Capacity of ethanol elimination: ~10 g ethanol/hr/adult man
The rate of decline in blood ethanol level is steady: 0.15 0.20 g/L in each hour.
V. Change in elimination kinetics from FIRST- to ZERO-order B. PHARMACOKINETIC ANALYSIS OF PCvsTC
EXAMPLE: An imaginary drug is given i.v. in 5, 10, 40, and 100 mg/kg doses. The
plasma conc of the drug is measured periodically and plotted against time in a semilog I. Analysis of first-order drug elimination
graph (see the figure below, curves A-D). The plasma concentrations at time 0 (C0) ONE-COMPARTMENT MODEL, INTRAVENOUS ADMINISTRATION
and at 100 min after dosing (C100) are also determined (see the table below). The drug is administered i.v.
The body behaves as a single compartment for the drug
PRINCIPLE: The shape of the PCvsTC will indicate the elimination kinetics: CONDITIONS - into which the drug is injected,
As long as the PCvsTC is a straight line, the kinetics is FIRST-order, which implies see the
- in which the drug is instantly distributed, and
scheme
that the dose is NOT saturating and the elimination is NOT capacity-limited. below - from which the drug is eliminated (see the scheme below).
If the PCvsTC is a convex line, the kinetics is ZERO order, which implies that On plotting the plasma concentrations of the drug against time in a
the dose is saturating, i.e., the elimination mechanism (enzyme or transporter) works semilogarithmic graph, they will fall on a continuous straight line (figure).
at maximum capacity, thus the elimination is capacity-limited.
FIGURE: The four PCvsTCs indicate that the elimination kinetics of the imaginary drug
changes from FIRST-order (at the lower doses) to ZERO-order (at the higher doses).

DOSE C0 C100
100
mg/kg mg/L mg/L
A= 5 5 0.038
B = 10 10 0.076
C = 40 40 1.7 !
10 D = 100 100 30 !!

NOTE: PCvsTCs are commonly

plotted in semilogarithmic graphs,
in which the PCvsTC is a straight
1 line, i.e. linear, if the elimination
is of 1st order.
Let us characterize the drugs
kinetics with meaningful
parameters: C0, Vd, T1/2, and Cl

Hence, the 1st order elimination is
often called linear elimination,
whereas the 0-order elimination
0 .1 may be called non-linear
elimination.
0 20 40 60 80 100 120 140 160 180 200 220 240
TIME (m in)
The consequence of the change in the kinetics of elimination from 1st to 0-order:
As long as the elimination remains FIRST-order, the plasma concentration at a given time point
increases proportionally to the dose, which is commonly expected. Note that the C0 values for
all doses and C100 values for doses A and B indeed increased proportionally to the dose.
Once the elimination becomes ZERO-order, the plasma concentration at later time points (e.g. at
100 min in the example) increases MORE than proportionally to the dose (see this for doses C
and D in the table). Thus, the plasma concentration remains unexpectedly high for an
unexpectedly long time. For this reason, the drug may cause, unexpectedly, toxic effects!
For example, phenytoin, whose elimination becomes ZERO-order at a dose of >300 mg, may
cause sedation, nystagmus, cerebellar ataxia, ophthalmoparesis, and paradoxically, seizures.
C0 = the apparent conc of the drug at time 0. Determine it by extrapolation to time 0.
Vd = Volume of distribution
Vd is an apparent volume which the amount of drug in the body would occupy if it were
uniformly distributed at the same concentration as it is in the plasma.
Vd can be determined by:
Div Consider: at time 0: - the total dose is in the body
Vd = - the plasma concentration is C0
C0
Why is Vd meaningful? For at least four reasons:
1. Vd can be used to calculate the body burden of a drug = Vd CP
if one measures the plasma concentration of a drug (CP) and knows its Vd,
it is possible to calculate the body burden important to know it in intoxications.
EXAMPLE: Paracetamol-poisoned patient; measure CP at least at 4 hrs after intake
Plasma conc of paracetamol: CP = 0.2 g/L; its Vd = 1 L/kg (see next page table)
The body burden of paracetamol: 1 L/kg 0.2 g/L 70 kg = 14 g
It is known that the hepatotoxic dose of paracetamol is >12 g.
Therefore, this patient should be given the antidote N-acetylcysteine!
2. The value of Vd may indicate the water space in which the drug is distributed and Kel = Elimination rate constant
whether the drug accumulates in tissue(s).
Kel is the fraction of dose in the body (=body burden) that is eliminated per unit of time.
TABLE: Volume of distribution (Vd) of some drugs. Kel is constant as long as the drug is eliminated by a 1st-order process.
The table also contains some model compounds whose V d value is the measure of Kel can be calculated:
a water space in the body (E.C. = extracellular).
Kel = - slope . 2.3
Chemical/Drug Vd (L/kg) Distribution space
Dextran 0.04 Plasma water space Determine the slope of the PCvsTC plotted in a semilog graph by fitting a rectangular
Heparin 0.06 triangle to the straight line representing the PCvsTC (see fig. above). The slope is the
Furosemide 0.13 tangent of the angle of the triangle. It has negative value, as it is a downward slope.
Leflunomide 0.13
Aspirin 0.15 Kel has a unit of hr-1. Kel = 0.1 hr-1 means that 10% drug is eliminated hourly.
Inulin 0.17 E.C. water space
T1/2 = elimination half-life
Carbenicillin 0.18
Gentamicin 0.28 T1/2 is the time during which the plasma concentration of the drug decreases by 50%.
Ethanol 0.57 Total-water space Determination of T1/2: - graphically (from the graph see the figure above)
Isoniazid 0.67 - by calculation:
Paracetamol 0.95 0.693 NOTE: Half-life (T1/2) can also be calculated from the slope:
T = T1/2 = lg2 : -slope or T1/2 = 0.3 : -slope (see Appendix-III)
Thiopental 3 Kel
Digoxin 6
Donepezil 12 TISSUE T1/2 is constant as long as the drug is eliminated by a first-order process.
Imipramine 18 ACCUMULATION NOTE: For a drug that is eliminated by a zero-order process, the T1/2 is NOT constant,
Amiodarone 66 as the T1/2 decreases with time after dosing and increases when the dose is increased.
Chloroquine 200 Thus, a drug that undergoes zero-order elimination has no real T1/2.

NOTES: Why is T1/2 meaningful? For at least four reasons:

Low Vd may indicate that the drug cannot leave the plasma because it is an extremely large 1. The T1/2 indicates when the drug becomes eliminated from the body.
molecule (e.g. dextran) and/or highly charged (e.g. heparin).
TIME AFTER DRUG DOSE REMAINING DOSE ELIMINATED Rule: Practically, a drug is
Extensive plasma protein binding may also result in low Vd (e.g. furosemide PPB ~99%, leflunomide
ADMINISTRATION IN THE BODY (%) FROM THE BODY (%) eliminated in 4-5 half-lives
PPB >99.5%) if the drug (when unbound) has a poor diffusibility through cell membranes.
1 T1/2 50 50 see the table.
However, extensively plasma protein-bound drugs may still have high Vd, if the unbound drug has a 2 T1/2 25 75 Theoretically, a drug is
good diffusibility through cell membranes due to its high lipid solubility. Such a drug is, for example, 3 T1/2 12.5 87.5 never eliminated
amiodarone (PPB ~99.98%) and donepezil (PPB ~96%). 4 T1/2 6.25 93.75 completely.
Remember: Binding to plasma proteins is reversible, and the concentration of the bound drug is in
equilibrium with the concentration of the unbound drug. Therefore, if the unbound drug can readily 2. The T1/2 is also related to the duration of action of the drug.
move from the plasma into tissues, then the bound drug dissociates, permitting continuous tissue EXAMPLE: A i.v. gen. anesthetic is given in two doses. Calculate its duration of action based on the
uptake and even tissue accumulation. premise in the Awakening column. Does doubling of the dose double its duration of action?
Very high Vd (several L/kg), indicates that the drug accumulates in one or more tissue(s); DOSE, mg iv T1/2, min Awakening Duration of action Rule: Doubling of the dose
i.e. Ctissue > Cplasma. For explanation of high Vd in this condition, see the two-compartment model. 100 10 When 12.5 mg ? min increases the duration of
200 10 remains in the body ? min action only by 1 half-life!
3. The size of Vd influences the duration of elimination: The larger the Vd in which a
drug is distributed, the longer the time its elimination from the body takes. 3. The T1/2 indicates the time needed to reach the steady state on repeated drug
See under Clearance: T1/2 is directly related to Vd (and inversely to Cl). administration. Steady state occurs in 4-5 half-lives (see later).
4. The Vd is used to calculate the loading dose: DL = Vd Css 4. The T1/2 influences the fluctuation of the plasma concentration of the drug
See later, under Repeated drug administration. around the steady state concentration (Css), and therefore, the decision of the
clinician on the dosing interval (see later).
Cl = Clearance
Cl (as a pharmacokinetic index) is a volume, a part of the Vd, which is cleared from
the drug per unit of time (L/hr). (Physiologically, Cl is a plasma volume, as drugs are
cleared from the plasma.) As a general term, clearance is synonymous to elimination.
Illustration of clearance: Clearance mechanism = dipper + strainer.
They represent organs that can eliminate the drug
(e.g. liver and kidneys). The pot represents the body,
containing the Vd that is filled with drug molecules (or
peas; although you should imagine that the peas in
this soup do not settle, but fill the pot uniformly).
The dipper and the strainer remove the peas (drug
Cl molecules) from the pot (body, Vd). With regular and
continuous operation, the dipper keeps clearing a
small volume (Cl) of the pot (Vd) from the peas (drug)
that is equivalent with the volume of the dipper.
Vd The volume of the dipper (that dips into the pot, the
Vd, at each unit of time) represents the clearance (Cl,
as a pharmacokinetic index).
Determination of Cl by two methods:
Method 1 is based on the definition: As Kel is the fraction of the dose eliminated per
unit of time, a Kel fraction of the volume of distribution is cleared in each unit of time.
Vd
Cl = Vd . Kel Cl = Vd . 0.693 T1/2 = 0.693 .
T1/2 Cl
NOTE: In the formula above (left), Kel can be substituted with 0.693 : T1/2. Then the new formula
(middle) can be rearranged to express T1/2. From this third formula (see above, right), you can realize
an important relationship:
The larger is the Vd (the pot) or the smaller is the Cl (the dipper) of a drug,
the longer it takes to eliminate the drug. In other words, the T1/2 may become longer if the
drugs Cl decreases, or its Vd increases.
To stay with the figure: The smaller is the volume of the dipper or the larger is the volume of the pot,
the longer it takes to remove all peas (or, say, half of the peas) from the pot (the longer is the T1/2). It
is also easy to realize that initially (when the pea soup is thick) one can dip out more peas than later
when the soup becomes thin; i.e. the elimination of the peas from the pot is concentration-dependent,
the kinetics is FIRST-order. Have you thought about this when serving yourself from a pea soup?
Method 2 is analogous to the calculation of urinary (or renal) clearance:
AU : T AB : T
Renal clearance, ClR = Total body clearance, Cl =
CP CP
ClR = The amount of drug excreted in Cl = The amount of drug eliminated by the
urine (AU) per unit of time (T) divided by body (AB) per unit of time (T) divided by
the plasma conc. (CP) at mid-time. the plasma conc.(CP) at mid-time.
The formula on the right can be further simplified if the drug is dosed i.v. and we
periodically determine its plasma concentration until the drug is eliminated (i.e. for at
least 4-5 half-lives), using the formula on the next page.
Total body clearance (Cl): Divide the i.v. dose (Div; i.e. the amount of drug eliminated
from time 0 to infinity) by the area under the PCvsTC from time 0 to infinity (AUC0-):
D NOTE: This formula is model-independent, whereas the formula
Cl = AUCiv
0-00 Cl =Vd Kel can be used only for the one-compartment model.
The total body clearance (Cl) can be regarded as the sum of the organ clearances:
Cl = ClR + ClH + ClX + ClY
Of these organ clearances, only the renal clearance can be determined conveniently.
The difference between the total body clearance (ClB) and renal clearance (ClR) is the
non-renal clearance (ClNR):
Cl ClR = ClNR
ClNR usually approximates the hepatic clearance well. However, if ClNR is larger than
the hepatic plasma flow, then organs other than the liver must also contribute to ClNR.
The hepatic blood flow is ~1.5 L/min; hepatic plasma flow is ~0.8 L/min.
What is the practical use of drug clearance?
If the Cl of the drug is known, we can calculate:
1. The dose rate (DR) that is necessary to reach and maintain an average steady-
state concentration between dosing times when the drug is dosed in regular intervals
or by continuous infusion (see in detail under repeated dosing).
Consider: If Cl is a volume (within the volume of distribution) which is cleared of the
drug per unit of time and if one wants to maintain an average steady state
concentration (Cav) in that volume, then the amount of drug to be administered per unit
of time (DR):
DR = Cl . Cav
2. The average steady-state concentration (Cav) that can be reached when the drug
is administered at a certain dose rate (DR) rearranged from the preceding formula:
DR
Cav =
Cl
The formulae above can be further rearranged to express the drug clearance:
DR
Cl =
Cav
This formula permits one to determine the Cl of a drug experimentally, provided the drug can be
infused i.v. and its plasma concentration can be measured, using the following procedure:
The drug is infused at a known rate (DR) and its plasma concentration is measured periodically.
When the steady-state concentration is reached (i.e. when the concentration no longer changes) the
DR (mg/min) at steady state is divided by the plasma concentration at steady state (Cav; mg/L) to
obtain the Cl (L/min). ADVICE: Consider this again when you have learnt about repeated drug
administration (see below).
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Those interested in where numbers 0.693 and 2.3 come from should read Appendix-III.
II. Analysis of first-order drug elimination Analysis of ABSORPTION of the drug by the method of residuals steps:
ONE-COMPARTMENT MODEL, ORAL ADMINISTRATION Extend the elimination section of the PCvsTC to the Y axis (dotted line with circles).
Subtract the measured values of the PCvsTC in the absorptive phase (rising solid
The PCvsTC after oral administration is composed of two phases (sections):
line) from the virtual concentrations on the dotted line to obtain the concentration
the absorptive phase analyzed to obtain the absorption parameters
differences.
the elimination phase analyzed to obtain the elimination parameters
Plot the conc differences against time to obtain the dashed line with diamonds.
EXPLANATION: The measured concentrations on the absorption section of the
PCvsTC (rising solid line) result from both absorption and elimination (A+E) of the
drug, whereas the virtual concentrations on the declining dotted line represent values
resulting only from elimination (E), as if an instantaneous absorption had been followed
by elimination. Therefore, the subtraction yields the negative absorption values:
E - (A+E) = -A
By plotting the differences, they will fall on a descending line (dashed line with
diamonds) whose slope is the same as the slope of an inverted, i.e. positive
absorption line would be, which would result if only drug absorption occurred, without
elimination taking place simultaneously. Therefore, from the slope of this generated
line (dashed line with diamonds) we can calculate the absorption rate constant (Kab)
and absorption half-life (T1/2 ab) see in the box right to the figure.
Kab represents the fraction of the dose absorbed per unit of time (its unit is hr-1),
T1/2 ab is the time during which half of the dose is absorbed.
Determination of Kab and T1/2 ab is useful when quantitatively comparing oral formulations containing
the same drug in order to decide which of the preparations ensures the most rapid drug absorption.

F = oral bioavailability which is the fraction of the oral dose that reaches the systemic
circulation (see also under Absorption of drugs). F is determined as follows:
AUC
Analysis of the ELIMINATION of the drug: F = AUCp.o.
i.v.
For calculating the descriptors of elimination (i.e. Kel and T1/2 el), the slope of the
elimination section of the PCvsTC* should be determined. For this purpose, a where AUCi.v. is the area under the PCvsTC from time 0 to infinity after i.v. dosing.
rectangular triangle is fitted to that section of the curve and the slope is calculated by
the formula in the figure. Thereafter, Kel and T1/2 el can be calculated as follows: AUC = area under the PCvsTC
- Determination of AUC:
Kel = - slope . 2.3
* We should select the section of the PCvsTC
where absorption has already been completed. AUC0- after oral administration may be determined graphically,
Absorption becomes completed in 4-5 absorption by dividing the AUC into trapezoids, and then summing up their areas.
half-lives (T1/2 ab) after drug administration. See
0.693 next page for T1/2 ab determination. Alternatively, AUC0- after oral administration may be calculated:
T1/2 =
Kel
Z Z
AUC0-00 = -
K el Kab
For calculation of Cl, the following formula is used:
Z is the common intercept of the two auxiliary lines on the Y axis (see figure).
F .Dp.o. F = oral bioavailability (see next page)
Cl =
AUC0-00 - The unit of AUC: AUC has units of concentration time.
For example, mg hr/L (or mg hr L-1).
where Dp.o. is the oral dose and AUC0- is the area under the PCvsTC from time 0 to
infinity (in practice at least for 4 T1/2). For determination of AUC0-, see the next page.
III. Analysis of first-order drug elimination
ONE-COMPARTMENT MODEL, REPEATED DRUG ADMINISTRATION
1. The steady state
When a drug is given repeatedly at regular intervals, the dosing interval (T)
influences the amount of drug in the body and the shape of PCvsTC.
If the dosing interval is 4T1/2 or longer (i.e. the 2nd dose is given when the 1st dose
has been eliminated), the PCvsTCs after the 1st and 2nd doses will be similar:
If the dosing interval is shorter than 4T1/2 (i.e. the 2nd dose is given when the 1st
dose has not been completely eliminated), then the PCvsTC originating from the 2nd
dose will be partially superimposed on the PCvsTC of the 1st dose, and the amount
of the drug in the body (called body burden) will increase:
However, neither the plasma concentration, nor the body burden of the drug keeps
increasing indefinitely after repeated dosing with dosing intervals shorter than 4T1/2!
Instead, after a certain time, a steady state (SS) is established. During the SS, the
actual plasma concentration of the drug oscillates around an average steady state
concentration (Css), reaching maximum levels after dosing (Cmax) and minimum levels
before the absorption of the next dose begins (Cmin).
EXPLANATION for SS: The rising plasma concentration before SS indicates that the rate of drug
intake exceeds the rate of elimination. However, if the plasma concentration increases, the rate of
elimination will also increase, because the elimination follows FIRST-order (or concentration-
dependent) kinetics! Therefore, the rate of elimination gradually approaches, and finally matches, the
rate of intake. At this time (steady state), the plasma concentration of the drug reaches a plateau with
constant average Css, Cmax and Cmin values.
Three rules for steady state:
1. After repeated drug administration at a constant dose rate, Css becomes
established in 4-5 T1/2.
2. Css is directly related to the dose rate (DR) and inversely related to the clearance of
the drug (Cl), and can be calculated as: Css = DR/Cl
3. The size of fluctuations in plasma concentration at SS (i.e. CmaxCmin) is directly
related to the dosing interval (T) and inversely related to the elimination T1/2.
2. Pharmacokinetic objectives of repeated dosing
Objective-1: to establish Css in the therapeutic window.
The fluctuations in plasma conc around Css, including Cmax and Cmin, should be kept in
the range of therapeutic drug conc range or therapeutic window (the range between
the minimal toxic concentration and minimal therapeutic conc of the drug).
If the therapeutic window of the drug is narrow (e.g. digoxin):
The dose rate (DR) should be selected so that Css, Cmax, Cmin should remain in the therapeutic
window. For this purpose, the dosing interval (T) should be sufficiently short (relative to T1/2) to
minimize fluctuations in the plasma conc. of the drug.
If the therapeutic window of the drug is wide (e.g. H2-rec antagonists):
The single dose can be relatively high and the dosing interval long (relative to T1/2), so that the
plasma concentration of the drug should well exceed the minimal therapeutic concentration.
Objective-2: to establish the therapeutic Css within a reasonable time.
The Css should be brought into the therapeutic window within a reasonable time (urgently, if urgent
effect is needed). However, this takes 4-5 T1/2!
If the T1/2 of the drug is not too long (compared to the urgency of treatment), repeated dosing with a
constant DR is appropriate.
If the T1/2 of the drug is long (e.g. digoxin 2 days, leflunomide 2 weeks), it would take unduly long
time to reach the Css with a constant DR.
How to reach therapeutic drug concentration (Css) soon if the drug has a long T1/2?
Give first a large loading dose (DL) and later smaller maintenance doses (DR).
Calculation of the LOADING DOSE (see figure below):
DL = Vd Css For oral dose: F DL = Vd Css DL = (V
Vd Css) : F
That is, the loading dose is the amount of drug that fills up the V d with the drug at Css.
Therefore, we want to fill up the pot with peas! see the figure below.
Calculation of the MAINTENANCE DOSE (see figure below):
DR = Cl Css For oral dose: F DR = Cl Css DR = (C
Cl Css) : F
That is, the maintenance dose is the dose rate (DR) that is necessary to steadily maintain the drug at
Css in the volume that is continuously cleared of the drug by the elimination mechanisms of the body.
This volume is the clearance (Cl)!
Therefore, we want to fill up the volume of the dipper with peas! see the figure below.
 IV. Analysis of first-order drug elimination
LOADING DOSE (DL) TWO-COMPARTMENT MODEL, INTRAVENOUS ADMINISTRATION
Depends on the Vd For many drugs, the plasma concentration vs time curve (plotted in a semilog graph)
we want to fill up the pot ! after i.v. administration is composed of two segments; the first with a steep slope and
the second with a less steep slope. This indicates that the body behaves for that drug
DL = Vd Css as two compartments:
Cl a central compartment (CC, or compartment 1), into which the drug is injected and
MAINTENANCE DOSE (DR) from which the drug is eliminated, and
Depends on the Cl a peripheral compartment (PC, or compartment 2), into which the drug moves from
we want to fill up the dipper! the CC and from which the drug returns to the CC (see the scheme below, right).
Vd DR = Cl Css

EXERCISE: Calculate the loading dose and the maintenance dose of digoxin
Pharmacokinetic data for digoxin:
Vd = 6 L/kg
Cl = 0.88 Clcreatinine + 0.33 ml/min/kg
This is an empirical formula for estimation of the total body clearance of digoxin in a patient. As
you see renal function (indicated by Clcreatinine) is an important consideration, because digoxin is
largely eliminated by urinary excretion.
F = 0.7
Css = 1.5 ng/ml (the desirable therapeutic plasma concentration of digoxin)

Data of the patient to be treated:

Body weight = 75 kg
Clcreatinine = 100 ml/min

Results calculated (Check them for correctness!):

DL = 1 mg
DR = 0.35 mg/nap ~1.5 tablet/day (one tablet contains 0.25 mg digoxin)
The loading dose of drugs is typically single dose. For digoxin, however, the loading
dose is often given as 4 divided doses in 24 hrs (e.g. 0.5 + 0.25 + 0.125 + 0.125 mg).
The narrow therapeutic window of digoxin explains this cautious administration. As
distribution of digoxin in its Vd takes time, early after dosing when the dose may still
distribute largely in the blood and the highly perfused organs, such as the heart, the
cardiac digoxin concentration may be excessively high (causing harmful effects, e.g.
AV block) if the full loading dose were given at once. This is avoided by giving the
loading dose in parts.
Why do we see two slopes on the plasma disappearance curve?
We measure drug concentration in the blood plasma that is part of the CC.
Initially, the drug concentration in the CC declines rapidly because of two processes
taking place simultaneously:
Elimination of the drug from the central compartment
Transfer of the drug from the central to the peripheral compartment
Later, when equilibrium is established between the CC and PC, the net drug transfer
from the CC to the PC stops. Thereafter, the decline of drug concentration in the CC
results solely from elimination (however, this decline may be limited by the return of the
drug from the PC to the CC if that is slower than the elimination).

A useful formula to calculate the body burden at steady state (BBss) after repeated oral Accordingly, the drug disappearance can be divided into two phases:
dosing: Distribution phase (from time 0 till the net transfer to the PC stops) = phase
Disposition phase (after the net transfer to the PC stops) = phase
BBss = (F DR T1/2) : 0.693
This formula can be deduced from the following formulae already discussed:
BB = Vd Css Css = F DR : Cl Cl = Vd Kel Kel = 0.693 : T1/2
Analysis of the drug disappearance curve by the method of residuals steps:
Extend the slope of the disposition section of the PCvsTC () to the Y axis to create
a dotted line with virtual concentrations on it and with intercept B on the Y axis.
Subtract the virtual concentration values on the projected segment of the line (dotted)
from the measured concentrations during the phase (solid line).
Plot the concentration differences against time to obtain the dashed line with
intercept A on the Y axis.
CALCULATIONS:
Calculate the hybrid rate constants:
- from the slope of the derived dashed line in the phase (see figure)
- from the slope of the straight section of the PCvsTC (solid line) in the phase: fig
C. APPENDIX
I. Interpretation of pharmacokinetic parameters Examples
Study the relationship between the various pharmacokinetic (PK) parameters of drugs as well as the
relationship between PK parameters and the doses of drugs in the concrete examples below.
Note that variations in PK parameters of the selected calcium channel blockers more or less
explain the differences in their doses: nifedipine is more rapidly eliminated (because of its much
smaller Vd), therefore it is administered in a larger dose than isradipine and felodipine.
In contrast, the variations in PK parameters of two loop diuretics alone do not explain the
differences in their doses: furosemide is less rapidly eliminated, yet it is given in at least 40 times
larger dose than bumetanide. The dose difference must be due largely to pharmacodynamic
difference between furosemide and bumetanide (i.e. higher potency of the latter drug to inhibit the
Na+K+ 2Cl- symporter in the ascending loop of Henle).

From intercepts A, B and hybrid rate constants , , calculate the rate constants: 1. Pharmacokinetic parameters for some Ca channel blockers. Observe the relationship between
- Kel: Elimination rate constant (see the formula below) their volumes of distribution (Vd) and elimination half-lives (T1/2). Also notice their clearances.
- K12: Distribution rate constant for drug transfer H
N H3C
H
N CH3 H3C
H
N CH3
H3 C CH3
from the central (1) to the peripheral (2) compartment (see the formula below)
- K21: Distribution rate constant for drug transfer CHEMICAL
H3 CO O
CH3
H3 CO O CH3 H3CO O CH3

from the peripheral (2) to the central (1) compartment (see the formula below) FORMULA O O O O CH3 O O
NO2 N Cl
From , calculate disposition (or biological) T1/2 of the drug (see the formula below) O
N Cl
From B and the iv dose, calculate the volume of distribution: Vd (see the formula below) Drug nifedipine isradipine felodipine
Vd L/kg 0.8 4 10,1
From the i.v. dose and the area under the PCvsTC (AUC0-), calculate clearance: Cl
Cl mL/minkg 7,0 10 12,1
AUC0- may be determined T1/2 hour 2,0 8 14,1
- graphically, by dividing the AUC into trapezoids, and then summing up their areas PPB % 96,0 97 99
- by calculation from A, , B, and (see the formula below) F % 50,0 19 15,1
Dose (1x) mg 10-20 2.5-5 2.5-5
Dosing daily 2x 2x 2x

2. Pharmacokinetic parameters for two loop diuretics. Observe the relationship between their
clearances (Cl) and the elimination half-lives (T1/2). Notice that their volume of distribution (Vd) is
similar. The huge difference in their dose has no pharmacokinetic basis; thus it must have a
pharmacodynamic basis, i.e. higher potency (lower IC50) of bumetanide than furosemide as an
inhibitor of Na+K +2Cl- symporter in the ascending loop of Henle.
O O
O O HOOC S
HOOC S NH2
CHEMICAL NH2

FORMULA O O
CH2 NH Cl
H3C NH

Drug furosemide bumetanide

Vd L/kg 0.13 0.13
NOTES: 1. The larger is the quantity of the drug which accumulates in the peripheral compartment, Cl mL/minkg 1.70 2.60
the lower is the B value (the intercept on the Y axis see the figure) and the larger is the Vd. This T1/2 hour 1.30 0.80
explains the extremely high Vd values for some drugs (e.g. amiodarone, chloroquine) which avidly PPB % 99 99,
accumulate in tissues (see the table containing the Vd of drugs above). F % 71 81
2. Compare the formulae marked with the asterisks to the formulae of T1/2 and Vd for i.v. dosing, one- Dose (1x) mg 40 0.5-2
compartment model to see the similarities and differences.
Dosing daily 1-2 x 1x
II. Calculation of hemodialysis and hemoperfusion clearance of drugs
Hemodialysis (HD) and hemoperfusion (HP) are extracorporal elimination techniques
to remove chemicals from the blood of the intoxicated patient. (HD is most often used
in renal failure to remove endogenous waste products from the blood.)
As shown in the scheme, in HD, the
V = plasma patients blood (usually from an AV
conc of the fistula) is pumped at 400 ml/min into
drug here the dialyzer containing semi-
permeable membrane tubing
immersed into the dialysis fluid that
flows opposite to the blood inside the
dialysis tubing (counter-current
dialysis). The toxicant diffuses from
the blood, through the pores of the
dialysis membrane, into the dialysis
fluid.
A = plasma
conc of the In HP, the blood of the patient is
drug here
pumped (perfused) into an
adsorbent-filled cartridge, which
removes the toxicant directly from the
F = plasma blood.
flow rate
These procedures require
heparinization of the patient.
The HD- or the HP-clearance of a drug (i.e., the volume of plasma from which the drug
is cleared by the hemodialyzer or the cartridge per minute, ml/min) can be calculated.
Three data are needed: (1) the plasma concentration of the drug in the arterial line (A,
mg/mL), i.e. before the dialyzer or the cartridge, (2) the plasma concentration of the
drug in the venous line (V, mg/mL), i.e. after the dialyzer or the cartridge, and (3) the
plasma flow rate into the dialyzer or cartridge (F, mL/min). From these data the HD- or
the HP-clearance of a drug is calculated as follows:
Cl = F (A-V)/A
where (A-V)/A is the extraction ratio that indicates the fraction of drug extracted by the
hemodialyzer or the cartridge in the hemoperfusion system. To calculate the plasma
flow rate, read the blood pumping rate and multiply it with 1 minus the Htc value.
Lithium is the most dialyzable toxin known, due to its water-solubility, low molecular weight, negligible
protein binding, and Vd similar to that of the total body water space. Thus, hemodialysis is the
treatment of choice for severe lithium intoxication. The dialysis-clearance of lithium may be as high as
70 to 170 mL/min. In comparison, the urinary clearance of lithium is only 10 to 40 mL/min in the urine
(due to extensive renal tubular reabsorption of Li+). Also dialyzable are methanol, ethylene glycol,
metformin, salicylate, Ba2+.
The extraction ratio for hemoperfusion approximates 1.0 for some poisons (before the cartridge
becomes saturated, which typically occurs after 4 hr-long use of the cartridge). Therefore, with a new
cartridge the drug clearance rate approaches the rate of plasma flow through the hemoperfusion
circuit. Examples for drugs removable by HP: carbamazepine, glutethimide, theophylline, digitoxin,
phenobarbital, procainamide, valproic acid.
III. Where do 0.693 and 2.3 come from in equations T1/2 = 0.693 : Kel
and Kel = -slope 2.3, respectively?
1. The origin of 0.693 in the equation T1/2 = 0.693 : Kel
When the elimination kinetics is of FIRST order, the decrease of plasma concentration
can be described by an exponential equation. Therefore, the plasma concentration C
at time T can be calculated based on the following equation (which is similar to the one
that describes the decay of radioactivity, another 1st-order process):
C = C0 e-Kel T
where C0 is the apparent concentration of the drug at time 0, and C is the plasma
concentration of the drug after time T, and Kel is the elimination rate constant (see Part
B.I.). The equation can be arranged into the following forms:
lnC = lnC0 Kel T
lnC lnC0 = -Kel T
C
ln = -Kel .T
C0
From the last equation, we can deduce the relationship between the elimination half-
life (T1/2). Obviously, after T1/2 time C : C0 = 1/2, therefore:
1
ln = -Kel .T1/2
2
Furthermore, ln1/2 = -0.693, thus:
-0.693 = -Kel T1/2
0.693 = Kel T1/2
0.693
T1/2 =
Kel
REMINDER:
The common logarithm (lg or log) of a number is its logarithm to the base 10. The common
logarithm of x is the power to which 10 would have to be raised to equal x. For example, the
logarithm of 1000 to base 10 is 3, because 10 to the power 3 is 1000: 1000 = 101010 = 103
The natural logarithm (ln) of a number is its logarithm to the base e, where e is approximately 2.72.
The natural logarithm of x is the power to which e would have to be raised to equal x. For example,
ln7.5 is 2.0149, because e2.0149 = 7.5
Some values used: ln0.5 = -0.693; ln2 = 0.693; lg2 = 0.301; ln2 : lg2 = 2.3
2. The origin of 2.3 in the equation K el = -slope 2.3 IV. Another way to plot the PCvsTC: Plotting the lg concentrations in a normal
graph rather than the concentrations in a semilog graph get C0 and the slope easily
By rearranging the equation Kel = -slope 2.3, the slope of the logarithmic (lg) plasma
concentration versus time curve can be determined as follows: FIGURE: This graph is a variation of
-Kel the graph presented in under B.I.
slope =
2.3 In that graph the plasma
concentrations are plotted against
The correctness of the formula for determination of the slope can be demonstrated in time in a semi-logarithmic graph (i.e.
the following deduction. Lets start out from the equation already familiar from a graph whose Y axis has a
Appendix II/1 (see above): logarithmic scale).
lnC = lnC0 Kel T In contrast, in the graph shown here
the logarithmic values (lg) of the
Lets transform this equation from the natural logarithmic (ln) form into its decimal plasma concentrations are plotted
logarithmic (lg) form. against time in a normal graph (i.e. a
graph whose Y axis has an arithmetic
It is known that lg x = ln x : ln 10 and that ln 10 = 2.3. scale). This presentation offers the
advantage of easy determination of
Therefore, to carry out the transformation, the previous equation is divided with 2.3: the C0 and the slope of PCvsTC.
K el . T
lgC = lg C 0 -
2.3
The main ADVANTAGE of plotting the lg plasma concentrations in a normal graph
This can be arranged into the following form: rather than the plasma concentrations in a semilogarithmic graph is that it makes it
-Kel . convenient to compute the slope and C0. This is done in the following steps:
lgC = T + lgC0
2.3 Run a linear regression analysis on the lg concentration values, fit a linear regression
line to the data points, and compute the equation of the line: y = m x + b.
It is easy to recognize that this is the equation of a straight line, which is usually written
as follows: The value of m in the equation represents the slope (which has a negative value).
The value of b in the equation represents the Y intercept, which is the logarithm of
y = m x + b (where m is the slope and b is the Y intercept of the straight line)
the plasma concentration at time zero (lgC0). From b (lgC0), C0 is obtained: C0 = 10b.
Therefore, log C0 represents b, which is the intercept of the straight line on the Y axis,
whereas (--Kel : 2.3) represents m (the slope) of the line. The slope can then be used to calculate:
1. The elimination rate constant (Kel), as described under B.I.:
Therefore, if Kel = -slope 2.3, or Kel = -slope ln10, or Kel = -slope (ln2 : lg2)
-Kel
slope = 2. The half-life (T1/2):
2.3
T1/2 = lg2 : -slope or T 1/2 = 0.3 : -slope
then
If you are interested to know how the formulas for T1/2 above were obtained, here is the deduction:
Kel = -slope 2.3

or simply: