Ii

Introduction to Pharmacokinetics

Advancements in biopharmaceutiCS have come a rate constant M. The magnitude of the rate con-
stant determines how fast the transfer occurs.
about largely through the development and appli-
The transfer of drug from blood to extravascular
cation of pharmacokinctics. PharmacokinetiCS is
fluids (i.e., extracellular and intracellular water)
the study and characterization of the time course
of drug absorption, disXribution, metabolism, and and tissues is called distribution. Drug distribution
is usually a rapid and reversible process. Fairly
excretion, and the relationship of these processes
quickly after intravenous (iv) injection, drug in the
to the intensity and time course of therapeutic and
plasma exists in a distribution equilibrium with
toxicologic effects of drugs. PharmacokinctiCS is
drug in the erythrocytes, in other body fluids, and
used in the clinical setting to enhance the safe and
effective therapeutic management of the individual in tissues. As a consequence of this dynamic equi-
librium, changes in the concentration of drug in
patient. This application has been termed clinical
the plasma are indicative of changes in drug level
pluirniacokinetics.
in other tissues including sites of pharmacologic
effect (hioreceptors).
DISTRIBUTION AND ELIMINATION The transfer of drug from the blood to the urine
or other excretory compartments (i.e., bile, saliva,
The transfer of a drug from its absorption site
and milk), and the enzymatic or biochemical trans-
to the blood, and the various steps involved in the
distribution and elimination of the drug in the body, formation (metabolism) of drug in the tissues or
plasma to metabolic products, are usually irre-
are shown in schematic form in Figure 1-1. In the
versible processes. The net result of these irre-
blood, the drug distributes rapidly between the
versible steps, depicted in Figure I—I, is called
plasma and erythrocytes (red blood cells). Rapid
distribution of drug also occurs between the plasma drug elimination. Elimination processes are re-
sponsible for the physical or biochemical removal
proteins (usually albumin but sometimes ci-acid
glycoproteins and occasionally globulin) and of drug from the body.
plasma water. Since most drugs are relatively small The moment a drug reaches the bloodstream, it
molecules they readily cross the blood capillaries is subject to both distribution and elimination. The
and reach the cxtracellular fluids of almost every rate constants associated with distribution. ho-
organ in the body. Most drugs are also sufficiently ever, are usually much larger than those related to
drug elimination. Accordingly. drug distribution
lipid soluble to cross cell membranes and distribute
throughout the body is usually complete while most
in the intracellular fluids of various tissues.
of the (lose is still in the body. In fact, some drugs
Throughout the body there is a distribution of drug
between body water and proteins or other macro- • attain distribution equilibrium before virtually any
molecules that are dispersed in the body fluids or of the dose is eliminated. In such cases, the body
appears to have the characteristics of a single com-
are components of the cells.
The body can he envisioned as a collection of partment.
This simplification however, may not be applied
separate compartments, each containing sonic frac-
to all drugs. For most drugs, concentrations in
tion of the administered dose. The transfer of drug
from one compartment to another is associated with plasma measured shortly after iv injection reveal a
 ttinphii naccuticS and ( !iniuiit I'harniacriklfltti(S

• Drug in Urine

Drug at Drug in Blood -----' Metabolite(s)

>
Absorption Site

-2
Drug in Other
Excretory Fluids

Drug in
rZ
Drug in
Other Fluids Tissues
k
of Distribution

absorption distribu n, and simrton.

Fig. i— i. Schematic representation of drug

The proportionality constant relating amount and

distinct distributive phase. This means that a meas-
concentration is called the apparent volume of dis-
urable fraction of the dose is eliminated before
tribution (V). In most situations, V is independent
attainment of distribution eqtiihbiiuin. These drugs
of drug concentration- Doubling the amount of
impart the characteristics of a mullicomPartillcnt
drug in the body (e.g.. by doubling the iv doso)
system upon the body. No more than two com-
usually results in a doubling of drug concentration
partments are usually needed to describe the time
course of drug in the plasma. These are often called in plasma. '['his is called dose proportiO no lay; it
the rapidly equilibrating or central compartment is often used as an indicator of linear p/iarotaco-
and the slowly equilibrating or jeripheral com- hiiii'tics.
The apparent volume of distribution is usually a
partment.
characteristic of the drug rather than of the biologic
PHYSICAL SIGNIFICANCE OF DRUG s\ stein, although certain disease states and other
CONCENTRATION IN PLASMA factors may bring about changes in V. The mag-
nitude of V rarely corresponds to plasma volume,
Blood samples taken shortly after intravenous
[Link] volume, or the volume of total body
administration of equal doses of two drugs may
water; it may vary from a few liters to several
show large differences in drug concentration de-
hundred liters in a 70-kg man. V is usually not an
spite the fact that essentially the same amount of
anatomic volume but is a reflection of drug distri-
each drug is in the body. This occurs because the
bution and a measure of the degree of drug binding.
degree of distribution and binding is a function of
- Acid drugs, such as sulhsoxazole, tolbutamide,
the physical and chemical properties of a drug and
or warfarin, are often preferentially hound to
may differ considerably from one compound to
plasma proteins rather than extravascular sites. Al-
another.
though these drugs distribute throughout body wa-
At distribution equilibrium, drug concentrations
ter, they have small volumes of distribution ranging
in different parts of the body are rarely equal. There
may be some sites such as the central nervous sys- from about 10 to 15 L in man. A given dose will
tem or fat that are poorly accessible to the drug. result in relatively high initial drug concentrations
There maybe other tissues that have a great affinity in plasma.
for the drug and bind it avidly. Drug concentrations On the other hand, many basic drugs including
at these sites may be much less than or much greater amphetamine, meperidine, and propranolol are
than those in the plasma. more extensively bound to extravascUlar sites than
Despite these complexities, once a drug attains to plasma proteins. The apparent volumes of dis-
distribution equilibrium its concentrat ion in
in the tribution of these drugs are large, ranging from 4
plasma reflects distribution factors and the simple to 8 times the voluitte of total body water (i.e.,
relationship between amount of drug in the body 180 to 3201. in a 70-kg man). The frequently small
(A) and drug concentration in the plasma (C) shown doses and large distribution volumes of these drugs
in Equation 1-I applies: often make their quantitative detection in plasma

A = VC (I-I) difficult.
 Introduction 10 l'hañnacokinctics 3

tion rate falls in parallel. The proportionality con

EE
stant relating rate and amount or concentration is
called a rate constant. Accordingly. the elimination
80
rate is written as follows:
0
dA
60 tLr:.kA (1-2)
0

40 where A is the amount of drug in the body at time

U t, A is the amount of drug eliminated from the
20 body (i.e., the sum of the amounts of metabolites
a- that have been formed and the amount of drug
excreted) at time t, and k is the first-order elimi-
4 8 12 16 20 nation rate constant.
The elimination rate constant is the sum of in-
Time (hrs)
di, ival rate constants associated with the loss of
Fig. 1-2. Time course of drug disappearance from the parent drug. For example, the overall elimination
absorption site (curve A) and appearance of eliminated drug rate constant (k) in the model depicted in Figure
in all forms (curve Q. The net result is curve B, which
I—I is given by.
depicts the time course of drug in the body.
(1-3)
PHARMACOKINETIC CONSIDERATIONS OF
Dimensional analysis of Equation 1-2 indicates
DRUG CONCENTRATIONS IN PLASMA that the units of k are reciprocal time
The plasma contains measurable quantities of
many endogenous chemicals. In healthy individ- Since there is a relationship beteen the amount
uals these biochemicals are present in concen1ra of drug in the body and the drug concentration in
lions that are reasonably constant, and it is appro- the plasma (Eq. 1—I), we may rewrite Equation
priate to speakQLcreatinine orhdiru leygls in
1-2 as
the plasma. Drug_ly .c 1 i co11ccotraLLonS-ifl thc
Tasma are rarely level. One usuall y finds different - d(VC) = —V = k(VC)
concentrations of drug in the plasma at different dt di
times after administration. These changes reflect
or
the dynamics of drug absorption, distribution, and
elimination (Fig. 1-2). -
dc
= kC (11)
di
Intravenous Administration
Integrating this expression between the limits t =
Absorption need not he considered shen a drug
0 and t = t yields
is given by rapid iv injection. As SOOn as the drug
is administered it undergoes distribution and is sub-
log log C, - '03
ject to one or more elimination pathways. The
amount of drug in the body and the drug concen-
Equation I—S indicates that a plot of log C \ersu\
tration in plasma decrease continuously after in-
will be linear once distribution equilibrium is
jection. At the same time, there is [Link] (ur-
ination of metabolites and continuous excretion of reached. The term C. is the intercept on the log
drug and metabolites. Eliminated products accu- concentration axis, on extrapolation of the lineal

mulate while drug levels in the body decline. segment to t = 0.

Figure 1-3 shows the average concentration of
Most drugs distribute rapidly so that shortly after
a semisynthctic penicillin in the plasma as a func-
iv injection, distribution equilibrium is reached.
tion of time after an intravenous injection of a 2-p
Drug elimination at distribution equilibri um is usu.-
close. The concentration values are plotted on. a log
kinetics. This mean.,,
that the rate of the proJs pdpötoflo the scale; the corresponding times a re plotted on a lin-
amount or concentration of substrate (drug) in the ear scale. The semilogarilhmic coordinates make
system. As drug concentration falls, the elimina- it convenient to plot first-order kinetic data for they
 Itiiph:irriiac&iuiiS and ( huh .l thai iit-: kiw i

_______l • -- t — -- i' tttiii 'a-Icr ioIij I : k Ii, ItJ:JC use of

I.e ullo ;t g re!;tion,lt a:
?00 T<_? Co k 069 1 ,'i, (I- J)
F
tile 11,df it' ( ' I tile JIIlg II.-.. he ti:r.e
-1 icqitired to reduce :!u: concentration k- c h': )
lo l r .nie r cr .5 deermitcI directl y from he pk-t tee
- R\ 7 S I0P k Fie. 1--3). In a !irst-ord:r lroec ss . the half-1jc is
2,303
ii icp-endeut f he die or initial plasill::
trltI''n. Oue hour is required to obsere a
50 du:'a ' t c-f sits plasitia cLiitccriiiOtTrii -( the semi-
s it U , tte :-cncilhn, nec distrihition tuildntm
IS ult:_tned It follos s that the elii-imn,i:ifl rate con-

slant ofihi-drun is equal ti 0.b93.t ori.6)3 ii

Krsissledeu of the half-life or Cliiiiin:iItrn ratC con-
tt1 ' hr stant of a drug is useful hccusc it piov!as a qiian-
CN tuative index of the persistence of,!: i-2 ill the beds-
For a dru g that distributes very rapidly after iv
r.;eeilon od is ei':mn:tted hs [irt trUer kinetics,
a
2 3 4 half tue dose sill he ia one halt-
TIME, hr life ifier aJmitti s :ralioii; ihiec-quarters of the dose
ill he eliuiinatei 11cr tsso half-uses. OIy akcr
r, i-. S hrnc 'ut t r v r .: -i c:rocrtrs - tar hall-I, e s -srI :uc ilLiji (it drer 'i tie hoel
[Link] aOsr a 2-g ii ',er curn C: ceiO!etcrs he reduced to less 1 5 .a onc-ieiimh the di. se . For tIns
ii a -it-o'sr mrrinr .'i1h a ha' . I t n of 1 I r.
reason, the hait-i:e : a U; Lu CSfl often he rciaicil
0 he dora ion -I .. effect and the frequency
01 dusta g -
he nCceih y of convcrtiniz aloes of C to
i_;t r• Shcr(- Term Con tat I Rota Intraveno us
\c-:crding to Equation 1 --5. the linear portion
Infusion
he uioaanthmtc pt of C versus i-has a
Fcsv dru g s should be given as a ripin intravenous
slope uorrecponding to - t i-) . 303 and an intercept,
Oil ii V-i\IS (IC., at I = 0), corrcspoiidiiig to C,,.
ujeL-tioru iholus) because of the potential toxicity
If a drug n crc :o ditnbu te almost immediately that maY [Link] dras that requite inirase-
after injection, C would be a function of the dose nous administration, including theopha lIme, pro-
aid the apparent volume of di-trihution Therefore, cainamtde - gentainicin, and many other atitihiotics
we would be able to calctil:tte V as follows; are given as short-tern coristrat rate ml:. ens ov'r
5 to 60 ruin, or lou;Uer. The following scheme d.
iv doc scribes this situatton:
V= (1-6)
Drug in Csiit Drug in k Lintimiarci
rSsL'rvalr l'ite - boiy -- LtIiig
For the data shuwn in Figure 1-3 we can determine
that C 200 trig/nil and that V = 10 L. The rite of cli :inge of 6 ,e a moo it of drug in the
This approach, however, is seldom useful; Equa- body (A) during uifusitn is eivetu by
tion 1-6 usually sives a poor estimate of V, always dA'dt = -- kA (1--8)
larger and sometimes substantially larger than the
true volume of distuibution. Equation 1- 6 assumes where k is the infusion rate expressed in amount
that drug distribution is immediate, whereas most per unit time (e.g -, mg 'in in), kA is we elimination
drugs require a finite time to distribute throughout rate, and k is the first-order elimination rate con-
the body space. Other method s to calculate V will stant This rdal iousli ip assumes that the drug
be described subsequently. reaches distribution equilthriutn 1itickly lrtegrat-
Although it is possible to calculate the elimi - ote l:qum;ution I--S front t 0 tot t )!elds
nation rate estiustairt front the slope of the line, it A = kJI -- exp( - kt)jk (1-9)
 Introduction to Pharmacoktnetics

since all other terms are known. This estimate may

he less than accurate but it is always better than
that provided by Equation 1-6.
The maximum or peak drug concentration its
z
0 plasma is always lower after intravenous infusion
than after bolos injection of the same dose. The
more slowly a fixed dose of a drug is infused, the
I- lower the value of C,,. Consider a rapidy dis-
z tributed drug with a half-life of 3 hr. A given dose
U) administered as an iv bolos results in an initial
C.)
z plasma level of 100 units. The same dose, infused
0 over 3 hr (T = tL) gives a C,,,, value of 50 units
C-)
(Cl2) infused over 6 hr (T = 2t), it gives a
concentration of 25 units (C,,/4). Also, since C_
is a linear function of k,,, doubling the infusion rate
Ix
C
and infusing over the same period of time (i.e.,
doubling the dose) doubles the maximum concen-
tration.

Ext (avasCUlar Administration

A more complex drug concentration-time profile
TIME
is observed after oral, intramuscular, or other ex-
Drug concentration iri P as during and after travascular routes of administration because ab-
Fig. 1-4.
a 1-hr constant rate intravenous in'..s :. The inset shows sorption from these sites is not instantaneous, nor
the same data plotted on semiloga' tic cc-:rdinates. does it occur at a constant rate. As shown in Figure
1-2, the rate of change of the amount of drug in
or the bod) (dA'dt) is a function of both the absorption
C = kl _.exp(ktkV (I-tO) rate (dA./dt) and the elimination rate (dA 5/dt); that
is.
According to Euation 1-10. drig concentration
in plasma increases during infusion. When the en- ,=- — (1-14)
tire dose has been infused at time I. drug concen- dt dt dt
tration reaches a maximum gisen by
or
= k,,1 - expi -kT)JikV (1-Il)
dC:=--I (I-IS)
and thereafter declines. The declining drug con- d d dij
centration is described by
where V is the apparent volume of distribution.
C = C,,exp(-kt1 (1-12)
When the absorption rate is greater than the elim-
ination rate (i.e., (lA1dt > (1A!dt), the amount of
or drug in the body and the drug concentration in the
log C,,,, -. (k 2.30 3 ) ( 1-13) plasma increase with time. Conversely, when the
log C
amount of drug remaining at the absorption site is
where t' = t -T. Equations 1-12 and 1-13 apply
when distribution equilibrium is esentially reached sufficientl y small so that the elimination rate ex-
ceeds the absorption rate (i.e., d.-\ [Link] > dAA/dt),
by the end of the infusion. A semilogarithmic plot
the amount of drug in the body and the drug con-
of C (post-infusion drug concentration in plasma)
centration in the plasma decrease with time. The
versus t' yields a straight line, from which the half-
maximum or peak concentiation after drug adruin-
life and elimination rate constant can be estimated.
istration occurs at the moment the absorption rate
The entire drug coucentrutiOfltime profile during
equals the elimination rate (i.e., dA A/ dt dAIdt).
and after a short-term infusion is shown in Figure
The faster a drug is absorbed, the higher is the
'-4.
maximum concentration in plasma after a given
Equation 1-lI may be [Link] to calculate V,
 ItIopharniaceutics aI1d (iirik,il i'firiac,kntks
6

dose and the shorter is the ii 1 ri c after administration .•r-,_

\ r4
-o
when the peak is observed
-S

E
First Order In—First Order Out cY' 50
s S.

Many drugs appear to be absorbed in a fir t- I . Start of post-

z absorptive phale
order fashion and the following scheme often ap- 0
plies:
cc Slope 2.303
', Eliminated I—
Drug at Drug in z
body drug uJ
absorption site U
Z 20
0
Under these conditions 0
(9 11/2
dAdt = kA; - kA (1-16) \
cc
0
where k is the apparent first-order absorption rate
constant, k is the first-order elimination rate con-
F3 1Z i
stant. A is the amount of drug in he body. and A5 4

absorption site. Inte- TIME, hr

is the amount of drug all
grating Equation 1-16 from t = 0 to t t and
Fig. 1-5. Typo ss-HogarithmiC plot of drug concentra-
converting amounts to concentrations results in the tion in plasma -.r g oral or intramuscular adrninistm
complicated equation slims n below: toll of a [Link] so:ed form of the drug.

C kF1)1exp( - kt) (I--I 7

nation rate, and Equation 1-15 reduces to Equa-
- exp(—kt)1V(k - k)
tion 1-4. The portion of it drug concentration in
where F is the fraction of the administered dose the plasma cr:is time curve, commencing at the
(D) that is absorbed and reaches the bloodstream. time absorption has ceased, is called the postab-
V is the apparent volume of distribution, and C is sorptive phase. During this phase. the decline in
the drug concentration in plasma any time it drug concentration with time follows first-order-
administration. Equation 1-17 is often used to de- kinetics. A semilogarithmic plot of drug concen-
scribe drug concentrations in plasma after extra- tration in the plasma versus time after oral or other
vascular administration. extravascular routes of administration usually
The absorption rate constant of a drug is fre- shows a linear portion that corresponds to the post-
quently larger than its elimination rate constant. In absorptive phase. A typical plot is shown in Figure
this case, at some time after administration, the 1-5; the slope of the line is equal to - k12.303.
absorption rate term in Equation 1-15 approaches The intercept of the extrapolated line (C 0 *) is a
zero, indicating that there is no more dnig available complex function of absorption and elimination
for absorption. and Equation 1-17 simplifies to rate constants. as well as the dose or amount ab-
sorbed and the apparent volume of distribution. It
C kFDIexp( - k t )] /V (k . - k) (1-18)
is incorrect to assume that the intercept approxi-
or mates the ratio of dose to volume of distribution
unless the drug is very rapidly and completely ab-
C C 0 exp( — kt) (1-19)
sorbed, and displays one-co m Part [lie nt character-
and istics (i.e., distributes immediately) . This rarely
occurs.
(1-20) Occasionally, the absorption of a drug is slower
log C = log C - litt
2.303 than its elimination, a situation that may be found
with drugs that are rapidly metabolized or excreted
Equation 1—I8 assumes that distribution equilib-
and with drugs that are slowly absorbed because
riuin is essentially reached by the end of the ab-
of poor solubility or administration in a slowly
sorption phase.
releasing dosage form. When this occurs, a semi-
When absorption is complete, the rate of change
logarithmic plot of drug concentration versus time
of the amount of drug in the body cqials the dim-
 Introduction Co Pharmacokinetics

(see Fig. I-5) after oral administration cannot be

used to estimate k or half-life because the slope is
related to the absorption rate constant rather than C
0
the elimination rate constant. The drug must, be 4-
administered in a more rapidly absorbed form or 0
given intravenously. 4-
C
Patient-To-Patient Variability C)
C
The time course of drug in the plasma afterad- 0
ministration of fixed dose may show considerable 0
intersubject variability. The variability after intra-
venous administration is due to differences between
patients in distribution and elimination of the drug. 0
These differences may be related to disease or con-
comitant drug therapy or they may be genetic in
origin. Variabi it is greater after intramuscular ad-
Time
min ist l ion because, in addition to diffeLence.S_1
jjriluhi.o&. nation, absorptionJflay-lx Fig. 1-6. The effects of absorption rate on drug concen-
variable. Differences in absorption rate after intro- tration-time profile. The same amount of drug was given
muscular injection have been related to the site of orally with each dosage form. the drug is absorbed most
injection and the drug formulation. Still greater rapidly from dosage form A. Drug absorption after admin-
variability may be found after oral administration. istration of dosage form C is slow and possibly incomplete.

The absorption fro m t

The dotted line represents the minimum effective concen-
tration (MEt) required to elicit a pharmacologic effect.
testinal -tract varies.
tstng, the tme'q centration (MEC) at the site of pharmacologic ef-
meals, the physical and chemical characteristicS.P
fect. Thus, the absorption rate of a drug after a
i druand the dosage form, among otlfac-,
LF single dose may affect the clinical response- For
tors. Simila', the amount of an oral dose of a example it is evident from Figure 1-6 that the
drug that is absorbed depends on biologic, drug,
more rapid the absorption rate, the faster is the
and dosage form considerations. Many commonly
onset of response. The drug is absorbed so slowly
used drugs are less than completely available-40
from dosage form C that the minimum effective
[Link] after oral admi nistratip because level is never attained. No effect is observed after
of incomplete rptiq presystemfliC met6-
a single dose, but effects may be seen after multiple
Tsm. doses.
The intensity of many pharmacologic effects is
Absorption Rate and Drug Effects
a function of the drug concentration in the plasma.
The influence of absorption on the drug concen-
The data in Figure 1-6 suggest that administration
tration-time profile is shown in Figure 1-6. Ad-
of dosage form A may evoke a more intense phar-
ministration of an equal dose in three different dos-
macologic response than that observed after ad-
age forms results in different time courses of drug
ministration of dosage form B since A produces a
in the plasma. The faster the drug is absorbed, the
higher concentration of drug. When dosage form
greater is the peak concentration and the shorter is
C is considered, it is clear that an active drug may
the time required after administration to achieve
be made to appear inactive by administering it in
peak drug levels. a form that results in slow or incomplete absorp-
• Many drugs have no demonstrable phanriaco-
tion.
logic effect or do not elicit a desired degree of
pharmacologic response unless a minimum con- BIOAVAILABILITY
centration is reached at the site of action. Since a
The bioavailability of a drug is defined as its rate
distribution equilibrium exists between blood and
and extent of absorption. Rapid and complete ab-
tissues, there roust be a niimiimunr therapeutic drug
sorption is usually desirable for drugs used on an
concentration in the plasma that corresponds to,
acute or "as needed" basis for pain, allergic re-
though may not equal, the mimsimnum effective con-
 ItjripfiatiiiiCctrttcs nnd CtnicaI t'rnracohilIciics

-
SpOnse, irisoninia, or other conditions. As sug-
gested in Figure I—fl, the more rapid the absorp-
tion, the shorter is the onset and the greater is the
Area - 1 —
kg-hr
intensity of pharmacolOgiC response. The efficacy ,Jmi
of a sinnie dose of a drug is a function of both the
rate and extent of absorption. In such cases, there
is no assurance of the biocquivalence of two dosage
\\
UEZ
forms of the same drug simply because the amount
of drug absorbed from each is equivalent; the ab-
sorption rate of drug from each drug product must
also he comparable. Rapid absorption may also
reduce the frequency and severity of gastrointes-
tinal distress observed after oral administration of ty
certain drugs, including aspirin and tetracycline,
3
by reducing the contact time in the gastrointestinal
TIME, hr
tract.
Usually, a useful estimate of the relative ab- rectilinear pot of drug concentration in
Fig. 1-7. Typical
sorption rate of a drug from different drug products the plasma following an oral dose. The area under the con-
or under different conditions (e.g., with food or - centration-time plot from t = 0 to t = 4 hrs is denoted by
without food) can he made by comparing the mag- shad ng.
nitude and time of occurrence of peak drug con-
centrations in the plasma after a single (lose.
plasma and the same AUC, the products are bio-
equi uleiit
Estimating the Extent of Absorption The area under it drug concentration in the
The extent of absorption or relative extent of plasma versus time curve has the units of conccn-
absorption of a drug from a product can be esti- tration-tinle (e.g.. .tg - hr/mi), and can be esti-
mated by comparing the total area under the drug mated by several methods. One method is to use
concentrati6ri in plasma versus time curve (AUC), a planimeter, an instrument for mechanically inCus-
or the total amount of unchanged drug excreted in uring the area of plane figures. Another procedure.
the urine after administration of the product to that known as the 'cut and weigh method," is to cut
found after administration of a standard. The stand- out the area under the entire curve on rectilinear
ard may he an intravenous injection tin orally ad- graph paper and to weigh it on an analytical bal-
ministered aqueous or water-miscible solution of ance. The weight thus obtained is converted to the
the drug, or even another drug product accepted proper units by dividing it by the weight of a unit
as a standard. When an iv dose is used as the area of the same paper (Fig. 1-7). The most com-
standard and the test product is given orally (or via mon method of estimating area tinder curves is by
means of the trapezoidal rule, which is described
some other extravascular route). we determine ab-
solute bionvailability. If, following equal doses of in Appendix 1.
the test product and the iv standard, the AUC values Sometimes, single dose hioavailahility studies
are the same, we conclude that the drug in the test are not carried out long enough to allow drug con-
product is completely absorbed and not subject to centrations to fall to negligible levels. We cannot
determine directly the total AUC, only the partial
prcsystenhiC metabolism.
Frequently, however, the standard iu an oral so- AUC. In this case, a widcly used method is to
lution or an established product. II, following equal determine the AUC from t = 0 to the last stitiiplrng
doses of the test product and standard, the AUC time (t*), by means of the trapezoidal rule, and to
values are the same, we conclude that the test prod- estimate the missing area by means of the equation
uct is 100Yc bioavailable , relative to the standard;
Area from t to . = C'fk (I 21)
we need use the word relative because we do not
know a priori that the standard is completely ab- where C* is the drug conecnlraliofl at t = t , and
sorbed or completely available. When two products
k is the apparent first-order elimination rate con-
produce the saute peak concentration of drug in
 liitriudurtioii to I'h:irii I [Link]

This area flhLi't be added t,) the area calculated Constant Rate Infusion
from time '_CrO to t to obtain the total area under
It is convenient Lu consider first the simpler ease
curve. of eontinJiiLs administration of a chug by flint-
The total area under the dru g level-Lime C61 NC
venous iiifu;ii,n tbis method ofdrcigadministratiott
for drugs eliminated by Iirst-ordcr kinetics is given
results in a plisna concentration-time profile that
by
is similar itt iltait y ways to that found OL) intermit
Aninuist OL drug reaching tent rcpetiti\e dosin g . Figure 1 - 8 illustrates the
lie blodstrcatii time course of drug concentration in plasma during
ALC - ---- (1-22)
and alter infussun
i on it act instant rate. At the outset -
dnii coneciitr,itin increases gradually but at a di-
It Iollosvs that the hin;ivailsbility l- nt si drug front
minishing rate. If itifuton is continued, drug con-
a drug product na b determined trout the cx-
oetitratioil eventually reaches a plateau or steady
[Link] -tae. A steady state is reached because We amount
- iAU•)i.:a of drug in the body reaches a level where the elim-
(1-23)
F -- ination rate, given by kA, is equal to the infusion
rate (k,). Whenever input rate equals output rate.
WIICtL equal doses are adiiiiiistcrcd. If different [Link] 0, dC dt = 0, and steady state exists.
doses of the product and stsind;srtl are given, the 13v considerin g Equation I—lU, which describes
area estimates should be scaled appropriately 10 dru g concenir:tiSon in plasma during constant rite
permit comparison under conditions of equivalent infusion, at it rues that are sufficiently large u that
doses, assuming AL'C is proportional to dose. expt -kt) ap1snaches zero, drug concentra'oIi at
The amount of drug excreted u neht nged in the steady state C . j is given by
urine (A) after administration is g iven ty

F - Dose kJi 1-24) k,,kV

where k is the un;sarv excretlou rat: cn ' Lant and

k is the overall elimination rate constant. It folloss s Since attainment of steady state often tep:Lsents
that the fraction of the dose absorbed from a drug the stabilization of a patient on a given course of
product relative to that absorbed from a standard therav, it is of interest to know how long it takes
may be calculated from the expression to reaLh steady state. For dru g s with pharmaco-
kinetic characteristics that can be described by a
<'rii one-compartment model (i.e., drugs that distribute
F= (1-25)
rapidly) we have a relatively simple relationship
The usefulness of Equation 1-25 depends on betseen attainment of steady state and the half-life
how much of the drug is eliminated by urinary of the drug. One half the steady-state conccntratio'i
excretion, the sensitivity of the assay for drug in is reached within a period of time equal to the half-
urine, and the variability in urinary output of the life of the drug. Following a period of infusion
drug. Many drugs are extensively metabolized and equal to four times the half-life, the plasma con-
little, if toy, appears unchanged n the urine. In centration is within 10 17c of the eventual steady-
such cases, bioavailahility is estimated from state concentration.
placma concentration data. If the time to reach steady-state represents an
unacceptable delay, one may wish to use art iv
CONTINUOUS DRUG ADMINISTRATION bolus loading dose or a series of iv bolos ininidoses
Most drugs are administered in a constant dose before starting the infusion. The loading dose is
given at regular intervals for prolonged periods of estimated from the ratio of infusion rate (k,) to
time. For some of these drugs a therapeutic plasma elimination rate constant (k). This approach woiks
concentration range has been identified. By pre- s'elI for most drugs given intravenously.
scribing a drug in an appropriate dosing regimen, If one knows the dnig level (C,) needed to pro-
the physician hopes to elicit a prompt and adequate duce a satisfactory response, Equation 1--26 can
clinical response. This is often pi edicated upon the be used to calculate the infusion rate (k,) needed
prompt attainment of adequate drug concentration to reach the desired lcvcl . Under these conditions,
in the plasma. - C,, - k - V and loading dose C - V.
 and Clinical pI,a,.n,acotdnelkc
10 Biopharmaccutics

Infusion

z
0

I—
z
W
C)
z
0
C-)

TIME, hr

Drug concentration in plasma during and after prolonged constant rate intravenous infusion. (From Gibald
Fig. 1-8. JAMA, 235:1987, 1976. Copyright 197E
M., and Levy, 6. Pharrnacckifletics in clinical practice. ii. Applications.
American Medical Association.)
where is the dosing interval. Equation 1-27 is
Repetitive Dosing too complicated to he of routine use; however, if
Turning now to the more common case of re- we could estimate the maximum and minimum
petitive oral administration of the same dose of a drug concentrations, we would be able to charac-
drug at regular intervals (Fig. 1-9), we find that terize steady state. Solving Equation 1-27 for the
although drug accumulate, in much the same way maximum drug concentration at steady state yields
as during constant infusion, drug concentrations in an equally complex equation. Better results are ob-
plasma during a dosing interval first increase and tained when we solve for the minimum concentra-
then decrease as a result of absorption, distribution, tion at steady state, particularly if we assume that
and elimination. The magnitude of the concentra- a (lose is always given in the postabsorptive phase
tion difference in a dosing interval depends on the of the previous (lose. Under these conditions,
rates of absorption and distribution and on the half-
life of the drug: this concentration difference in-
kFD cxp(—k'r)
creases with increasing absorption rate and de- (l—')
v(k, — c)[I- exp(—k'r)I
creasing hall-life. Drugs with long half-lives or
slow absorption show rather constant blood levels
Since the minimum drug concentration after the
at steady state.
Drug concentration at any time during a dosing first dose of it repetitive dosing regimen is given

interval at steady state can usually be described by by

the following equation:
= kFl) cxp( - k'r)IV(k -- k) (1-29)
kFl)exp(—kt)
V(k—k) 1 — cxp(—ki) (I-27) we can write a relatively simple expression for the
cxp( -kt) degree of drug accumulation during multiple dos-
ing by comparing ti l e minimum drug con,:cntralion
- I— cxpHkr)
 Introduction to Pharmacokinetics 11

CP
E
z In
0

lx
I—
z
LU
0
z
0
0

TIME, days

Cr. The masifllUrfl (C_.).

Fig. 1-9. Drug concentration in plasma durirg repetitive oral administration of 250 rrg every 6
mirsirrum (C.), and average () drug concertratioris at steady slate are noted. (From Gibaldi, M. and Levy, 0.: Phar-
macokineticS in clinical practice. II. Applications, JAMA, 235:1987, 1976. Copyright 1976, American Medical Associa-
tion.)

at steady state to that after the first dose. Dividing but they are given either several times a day or
Equation 1-28 by Equation 1-29 yields once a day. Drug accumulation may be substantial.
When appropriate, it has become increasingly
common to administer a drug once every half-life.
Accumulation = (1-30) The current use of theophylline, procainamidc
= I / L I —exp(kr)1 phenytoin, and tricyclic antidepressants reflects
this trend.
Therefore, by merely knowing the elimination rate
constant (k) or half-life of a drug we can predict
Average Drug Concentration at Steady State
the degree of accumulation for a given dosing reg- An alternative and simpler way of describing
imen. If a drug is given every half-life (i = tu2) steady state is to consider the average drug con-
the accumulation at steady state will be about 2-fold centration (C u ), which is analogous to the steady-
relative to the first dose. slate concentration during continuous infusion. If
Some drugs, including the penicillins and ccph- drug concentration during each dosing interval is
alosporins, are given less frequently than once viewed in terms of an average concentration, We
every lialf-life. These drugs have half-lives in the can express the intermittently administered dose in
order of 1 hr, but are usually given every 6 to 8 terms of an average dosing rate. For example, 100
hr. Virtually no accumulation is observed on re- nig given every 4 hr can be viewed as a 25 mg/hr
pealed administration. Many drugs, such as diaz- average dosing rate. When based on these consid-
epam, ainiodaronc, phenobarbital, and digoxin, are erations, Equation 1-26 for a constant rate intra-
given more frequently than once every half-life. venous infusion can be applied to the intermittent
For these drugs the hall-life is greater iliart one day oral administration of a drug with one additional
12 It IOj)h81 IiflCCiiiICS slid Clinical I 1 11,31nl1C(IkinCt cs

provision: alloss uicc must he made for the possi- for those drugs which distribute slowly or to which
bility that absorption of the drug is less than com- patients become accustomed only gradually. Cau-
tion should be applied at all times. With digoxin
plete. Then.
or digitoxin therapy, loading (or digitalization) is
C,, = F(avcrage (losing rate)fVk (1-31) almost always carried out with 3 or 4 divided doses
over the first 1 or 2 days of therapy.
where F is the fraction of the administered dose
Treatment of epileptic patients with phenytoin
that actuall y reaches the bloodstream. The prop-
is often initiated with a regular maintenance dose
erties and usefulness of ( ' s, are discussed in greater
divided or single, of 300 to 400 mg daily. When
detail in Chapter 2.
phenytoin therapy is begun in this manner, steady-
state plasma phenytoin levels are achieved after 7
Loading Dose
to 10 clays. Some clinicians believe, however, that
Whether a drug is given by continuous intra- in the patient with frequent seizures a delay in
venous infusion or by repetitive oral administra-
reaching the therapeutic steady-state phenytoin
tion, it usually requires about 4 times the half-life - plasma level may be detrimental because attacks
of the drug to reach an average concentration within may occur before the drug develops its full anti-
10% of the steady-state concentration. In some in- convulsant effect. Several clinical investigators
stances, this may represent too long a period to have suggested initial loading of selected patients
wait for optimum drug effects, and an initial load- with phenyloin.` 2 In one study,' 61 patients re-
ing dose is used ceived a 1-g loading dose of phenytoin followed
Assuming that it is clinically acceptable to do • by a constant daily maintenance dose of 300 to 400
this in a single dose, one can estimate a loading rug. Seizure control was obtained promptly in all
dose based on the usual maintenance dose and elim- patients who responded to the drug. Patients tol-
ination rate constant of the drug as follows: erated the loading doses well, and therapeutic
phenytoin levels were achieved rapidly. Studies in
Maintenance dose (13' children have confirmed the efficacy but have
Loading dose raised questions regarding the safety of this ap-
- I - exp( - kr)
proach.'
This loading dose ss ill provide a drug concentration It is well recognized that more than a week of
'r hr after administration that is equal to the mini- treatment with a given maintenance dose of gus-
mum drug concentration at steady state following ncthidine may be required to produce the maximum
repetitive administration of the maintenance dose. antihypertensive effect of this dose. This results
If a drug is administered every half-life, the ap- from the fact that elimination of the drug from the
propriate loading (lose is 2 times the maintenance body is slow (average half-life about 5 days). A
dose. Therapy with tetracycline ((L . = S hr) is often regimen has been devised for achieving the phar-
initiated with a 500-mg loading dose followed by macologic effects of guaneihidine relatively rap-
250 mg every 8 hr. idly. using the concept of loading and maintenance
The difference between loading dose and main- doses based oil kinetics of guanethidine elim-
tenance dose depends on the dosing interval and ination This regimen was tested in 6 hypertensive
the half-life of the drug. Digoxin, which has a half- patients Reduction of blood pressure was achieved
life of about 44 hr but is administered once a clay. with individualized divided loading doses of 150
is t y pically given as a loading dose of 1. 0 to 1.5 to 525 mg guanethidine administered over a period
nig followed by daily doses of 0. 125 to 0.5 tng; of I to 3 days. Maintenance doses ranging from
the ratio of loading dose to maintenance dose is 20 to 65 mg per clay were calculated from the
about 3 or 4. The half-life of digitoxin is about 6 loading dose by assuming a daily loss of about one
days: typically digitoxin therapy is initiated with a seventh of the body stores of drug. Satisfactory
loading dose of UI) to 1.6 mg followed by daily control of blood pressure was maintained following
doses of 0.1 to 0.2 rug; the ratio of loading dose the guanethidine load, without side effects.
to maintenance close is usually about 10. The
Dosing interval
smaller the ratio of dosing interval to half-life, the
larger is the ratio of loading close to maintenance The frequency of dosing is often based on tra-
dition and usage (e.g., the t.i.d. orq.i.d• regimen).
dose.
From ci ph t arrnacokiric'tic point of view, however,
Loading of- dru g s may he hazardous. panic u nil y
 Introduction to I'harmacokinetics 13

a rational dosing interval for most drugs approxi- men because it was easier to remember or easier
mates the biologic half-life. Thus, it has been found to take and more conve nic itt.
that the traditional 3-times-a-day dose of phcny- Less frequent dosing may not be feasible with
loin; a drug with an average half-life of about one sonic rapidly absorbed drugs that produce high
peak concentrations in the plasma, resulting in
day, is unnecessary in many palienls and that the
adverse effects. This prolilcin may he overcome
total daily dose can often he administered once a
by using slow-release dosage forms. Thus, slow-
day.' release forms may be rational even for some drugs
Similar conclusions have been reached with re- with long biologic hal f-I is cc. Presumably, once-a-
specttodosing ofgriscofulvin. Comparable steady- day dosing of griscolitivin and certain phertytoin
state plasma levels of griseofulvin are achieved products is well tolerated because these dru gs are
whether the drug is given in doses of 125 mg 4 absorbed rather slowly. Iligh doses of most ncu-
times a day or in a single daily dose of 500 mg.6 roleptics and tricyclic antidepressants tend to sedate
Apparently, treatment with griscofulvin can be and, for most patients, late evening administration
simplified to once-a-day administration With no of the total dose is preferable. This may offer the
loss of efficacy or safety. additional advantage of avoiding the need for a
Many neuroleptics and tricyclic antidepressants hypnotic drug.
have rather long biologic half-lives. Almost from
the beginning of psychoph armacothcrapy certain REFERENCES
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els, and toxicilr. Ards. Neural, 1i:'s52, 1964.
or q.i.d. division of drug administration is not as 2. Wilder. B.!.. Serrano. EL, au] Ramsay, R E.: Plasma
necessary as generally believed and that single diphen Its danmoin levels after lauding and maintenance
doses. Chi n. Pharmuacol. Ther., 11:797, 1973.
daily doses are sufficient for many patients, par- 3. Wilson, J.T.. t3djcr. B., and Rune, A.: Loading and con-
ticularly those on maintenance therapy.' sentionat done therapy with pherOtoin in children: Kinetic
For the past 15 years, the most commonly used profile of parent drug and main utietabotite in plasitta. Ctin.
Pharmaot. Thor.. 211:18, 1976.
dosage of allopurinol has been 100 mg 3 times a 4. Shand. D G, ci at.: A loading-maintenance regimen lor
day. Although the half-life of allopurinol is only more rapid initiation of the effect of nuanethidine. COn.
Pharmacol. Thor., 18:139, 1975.
about I hr, the half-life of its active metabolite, 5. Buchanan. R-A., ci at.: The iuetahottrn of diplicaIhy-
oxypurinol, is much longer, about 30 hr. In rec- dantoin (ditantin) follous ag once-daily administration.
ognition of this, it has been suggested that allo- Neurology. 22:1809. 1972.
6. Platt, D.S.: Plasmaconcertirationsof griseofutvmn inhuman
purinol be administered as a single daily dose. volunteers. Br. J. Dermatot., 83382, 1970.
When 300 mg of allopurinol given in a single daily 7. Ayd, F.D.: Once-a-day neuroteptic and tricyclic antide-
pressant therapy. Int. Drug Ther. Newsletter. 7.33, 1972.

I
dose was compared with 100 mg given 3 times a 8. BrewiS. I., Ellis, R.1.. and Scott, sr.: Single daily dose
day, i was found lobe equally effective in reducing of allopurinot. Ann. Rheum. l)is., 341:256, t975.
9. Rodman, OP., em at.: Allopurini't and gouty hapeniri-
and controlling uric acid levels and equally well cernia. Efficacy of a single daily dose. JAMA 231:1143.
tolerated. A more recent study confirmed these 1975.
[Link], \V.J,C., Turner, P., and Young, J.H.: Evaluation
S results and found that 27 of 33 patients preferred of once a day allopurinol administration in man. Br. J.
the once-a-slay regimen to the divided-dose rcgi- Clin. Pharmacol., 5.90, 1978