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Pharmacokinetics and Biopharmaceutics

Chapter · January 1994

DOI: 10.1007/978-94-015-8277-3_6

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CHAPTER 6

Pharmacokinetics and Biopharmaceutics

6.1. Pharmacokinetics and Biopharmaceutical Consequences of

Complexation of Drugs with CDs

Besides the stabilization of unstable drugs, the modification of the pharmacokinetic

and biopharmaceutical properties of a drug is the most significant effect of CD
complexation.
The first demonstrations of in vitro and in vivo effects of CD complexation on
pharmacokinetics/biopharmaceutics was published by Frornming and Weyermann
in 1972 [1, 2]. The dissolution rates of menadione and phenobarbitone from
j3CD inclusion compounds are higher than those of pure menadione and pheno-
barbitone. Salicylic acid/j3CD inclusion compound showed a significantly higher
bioavailability in human than pure salicylic acid.
The pharmacokinetics of a drug can generally be subdivided into the invasion
phase (drug release, absorption), the distribution phase and the elimination phase
(metabolism, excretion). The effects of CD complexation are decisively manifested
in the invasion phase.
Drug release, absorption and bioavailability of a perorally administered drug
depend on several factors; among them are the solubility, the dissolution rate, and
the rate of intestinal absorption. The solubility and dissolution rate of a drug -
beyond its fundamental chemical properties - primarily depend on crystal structure
and particle size. Therefore, identical doses of a drug may result in different blood
level curves, depending on the formulation of the drug.
The pharmacokinetic behaviour of a drug in the body can be described by
pharmacokinetic models. Such a model can also explain the various effects which
can be exerted by CDs. Figure 6-1 shows such a model for peroral administration,
e.g. a solid drug-CD inclusion compound in a tablet or a capsule.
If the drug is poorly soluble in water, i.e. kd < ka, dissolution is the rate
determining step: kd then has to be increased by micronizing the particles, by
preparing 'solid solutions' in hydrophilic matrices, by adding surface active agents,
or by forming less hydrophobic complexes, e.g. with CDs. It seems to be a

105
106 CHAPTER 6

[ CD - Drug]
solid

!kd

[ CD - Drug ] co + Drug
dissolved

t
absorption absorption
Fig. 6-1. Pharmacokinetic model.

universal experience that the dissolution rate, kd, and the solubility of hydrophobic
drugs increases considerably when their molecules are entrapped in the CD cavity.
The first step after the administration of a solid CD inclusion compound is
the dissolution of the complex in the gastric and intestinal juices. The dissolved
complex is in an equilibrium with the dissociated, 'empty' CD plus noncomplexed
drug molecule. Only the noncomplexed drug can be absorbed, not the intact
inclusion compound. A rapid absorption is therefore expected if the value of the
stability constant of the complex is low.
With a very stable complex, or by using a high CD concentration, the equilibrium
is largely shifted toward the complex formation; the concentration of absorbable
free drug is lower. In this case, absorption is the rate limiting step [3].
The absorption rate of drugs can thus be accelerated or retarded by appropriately
manipulating the complex dissociation equilibria. These modifications of the
pharmacokinetic processes and the influences on blood or plasma curves by CDs
can be simulated with a computer (Figure 6-2).
Complexes with lower stability constants result in a rapid increase in the blood
level and a high peak value. With increasing stability constant the degree of
dissociation decreases and a lower free drug concentration can be reached in the
gastrointestinal fluid. The blood level peak will be shifted towards higher values
on the time abscissa and a significant decrease in the peak height can be observed.
An enhanced biological response is, however, expected in all cases as compared to
PHARMACOKINETICS AND BIOPHARMACEUTICS 107

20 40 60 min 80
Fig. 6-2. Simulated blood level curves obtained after peroral administration of free drug or
its CD complexes with different stability constants K (M-1). Drug (D)/CD = 1 : 1. D: Drug
without CD.

the free drug.

On administering CD in excess, together with the CD complex of the drug, the
dissociation equilibria can be shifted toward a higher ratio of complexed drug in
the gastrointestinal fluid. These changes have a great influence on the shape and
peak height of the blood level curves, as can be seen from Figure 6-3 [3].
Such simulated blood level curves are only valid in animals or humans if the
correct and complete assumptions have been made. They are:
- only dissolved free drug molecules are absorbed;
- CD is absorbed neither in free nor in complexed form;
- the mechanism and the kinetics of the absorption process are not modified by
the presence of CD;
- no other reaction partners are involved in the reaction.
These assumptions do not correspond with reality in all details. One has, for
example, to consider that at the site of administration endogenous substances can
compete with the drug for the CD cavity. Therefore, such simulations can only give
a rough approximation of the pharmacokinetic behaviour of inclusion compounds;
but these are very important values. The stability constants of most CD inclusion
compounds have values that guarantee a sufficient amount of noncomplexed drug
108 CHAPTER 6

,....•...
_1:2
. ,
k-·,.'::"::-1 :1,5
0.6 ,
.;
'.',
'.,'..,
I »> •... ,., '.

." --1 ..1 ,.'~.,

o , ,', '"
'.
I,.,
,I ~"
----_"-"-
...••..
•..
_

.,
00- •• ------- •• --- ••

0.4 il
!I

.,I,i"l
0.2 K=1000 M-1
;,
~

(
40 80 120 rnm 160
Fig. 6·3. Simulated blood level curves after administering free drug or its CD complex with
solid CD in excess. D: Drug without CD.

being available for rapid absorption.

Very frequently, the CD complexation of a poorly soluble drug results in im-
proved bioavailability. This is generally based on the increase in the solubility and
dissolution rate of the drug.
The following examples will demonstrate this in greater detail. Given perorally
the DIMEB complex of o-tocopheryl nicotinate to dogs, the attained maximum
plasma level of the drug is about 17 times higher than after administration of an
equivalent dose of the drug alone. The relative bioavailability is 70 times as much
as that of the drug alone [4].
Spironolactone shows variable and incomplete peroral absorption, most likely
as a result of its poor solubility and dissolution rate. In a bioavailability study
with 12 volunteers, the mean quantity of the metabolite canrenone excreted after
48 h was 2716.4 u.g for the j3CD complex, 1939.9 fLg for a physical mixture, and
1279.6 fLg for spironolactone alone [5].
Imai et at. found a significant difference in the maximum serum levels between
PHARMACOKINETICS AND BIOPHARMACEUTICS 109

Table 6-I. Pharmacokinetic parameters of f1urbiprofen fol-

lowing peroral administration of f1urbiprofen and its CD com-
plexes to rabbits.

Compound AUCO-8 MRT

(J-Lg h mr ') (h)

Flurbiprofen 73.9 ± 8.4 3.67 ± 0.15

(3CD complex 136.7 ± 12.6 2.75 ± 0.11
TRIMEB complex 160.0 ± 7.4 2.83 ± 0.07

fturbiprofen and its complexes with j3CD and TRIMEB, respectively [6]. The Cmax
value is 14.2 jLg/ml after administration of fturbiprofen, while j3CD and TRIMEB
complexes result in the rapid appearance of fturbiprofen in the serum, showing Cmax
values of37.6 and 43.0 jLg/ml, respectively. The mean residence time (MRT) which
may represent the rate of bioavailability, is improved by inclusion complexation
(Table 6-1).
The AVC for j3CD and TRIMEB complexes up to 8 h post administration are
about twice that of fturbiprofen alone. However, no significant difference between
the pharmacokinetic parameters of the two complexes is observed upon peroral
administration (Figure 6-4).
A pharmacokinetic study of piroxicam in the steady-state in elderly subjects
and younger adults after administration of the j3CD complex confirms that the
complexed drug has the same pharmacokinetic behaviour in the steady-state as the
noncomplexed drug. The only difference is a reduction ofT max after administration
of the complex [7].
The bioavailability of ipriftavone is significantly enhanced by complexation with
j3CD after peroral administration to rats. Ipriftavone values after administering the
free drug: Cmax = 3.81 nmol/ml, AVC = 66.70 nmol h/ml; and after administering
the complexed drug: Cmax = 6.58 nmol/ml, AVC = 90.18 nmol hlml [8].
Bioavailability studies in rats show that the extent of absorption is identical in
respect of free ibuprofen and ibuprofen j3CD complex. However, the time to reach
peak plasma concentration for the complexed ibuprofen is 2.S-fold faster than the
drug alone [9].
The improved bioavailability of a drug can also be demonstrated by acute peroral
toxicity tests. Subcutaneously administered soluble nystatin/o-CD complex killed
90% of the animals at a dose of 20 mg/kg within 24 h, while even 200 mg/kg of free
nystatin resulted in no mortality during an observation period of one week. These
data show that a toxic dose is absorbed from subcutaneously administered soluble
110 CHAPTER 6

40

~
30
I

E
en
::l.. 20
~
- (1)

>
(1)

E 10
:l
L-

(1)
1I1

o 2 4 6 h 8
time
Fig. 6-4. Serum levels of fturbiprofen following the peroral administration of its CD complexes
to rabbits. 0 Flurbiprofen alone, • (3CD complex, 0 TRIMEB complex, n = 5.

nystatinfryCD complex, but not from a tenfold higher dose of free, insoluble nystatin
[10]. The pharmacokinetic and biopharmaceutical problems that are connected
with sustained release formulations are described in Section 8.8
At the time of writing, relatively little attention has been paid to competitive
complex formation, which probably plays a rather important role in the pharmacoki-
netics of CD-complexed drugs. The first hint of the existence of such competitive
reactions and their possible significance was published by Tokumura et al. [11].
The inclusion of cinnarizine in ,BCD increases the solubility of the drug but not
its bioavailability upon peroral administration to dugs. Enhanced bioavailability is
achieved only if the inclusion compound is administered together with a substance
which competes with ,BCD for complex formation in aqueous solution (Figure 6-5)
[12].
On simultaneous administration of DL-phenylalanine as a competing agent, the
AUC for cinnarizine is 1.9 and 2.7 times as large as those of the cinnarizinel,BCD
PHARMACOKINETICS AND BIOPHARMACEUTICS 111

GJ
01.\°
\1 '
0
-o Absorption
>

90.>
Dissolution GI Tract

---->
a Absorption

----
--.
Fig. 6-5. Process of drug absorption from CD complexes and the role of competing agent.
\II? CD;o Drug/CD complexvj Drug; ~~ Competing agent;\t;Competing agent/CD complex.

complex without a competing agent, and cinnarizine alone, respectively (Figure 6-

6). The enhancement of AUC and Cmax completely depends on the amount of D L-
phenylalanine. The minimum effective dose required of DL-phenylalanine in the
gastrointestinal tract might be 1 g for 50 mg of cinnarizine in the cinnarizine/,BCD
complex [12]. A similar effect was observed with L-isoleucine as competing agent,
and less pronounced with L-Ieucine [13].
Various constituents of meals and of secretions in the body are concerned with
the exchange of guest molecules from CD complexes. An example is the possible
interaction of bile salts with CD complexes in the duodenum, where large amounts
of bile salts are excreted from the gall bladder. ,BCD forms inclusion complexes
with bile salts in aqueous solution [14].
FrijIink [15] concludes, on the basis of his experiments on rectal drug absorption
from micro-enemas in humans that displacement reactions of the complexed drug
play an important role.
It might be expected that complexation of dissolved drug with CDs decreases the
absorption rate, especially because the dilution of the enema cannot be important,
since the volume of rectal fluid is only about 3 ml. A comparison of the absorption
profile of the ,BCD containing formulations with 0.5 mg diazepam (stability constant
of the complex 179 M-1) with that of 0.5 mg diazepam alone, demonstrates that, in
spite of the fact that up to 75% of the diazepam is complexed by ,BCD, absorption
is not decelerated. Even when an amount of 2 mg of diazepam is dissolved with
the help of CDs, no significant deceleration of drug absorption is observed. In the
2 mg formulation without CD, only 28% of the total diazepam is dissolved and this
112 CHAPTER 6

••
E 200 200
OJ
c
c~
a
0
•...
C
QJ
u 100 100
c
a
u
0
E
Vl
0
0.

o 2 4 6 h 8 2 4 6 h 8
time time
Fig. 6-6. Plasma concentration of cinnarizine (50 mg) after peroral administration of its
inclusion compound with and without DL-phenylalanine to dogs .• Cinnarizine; 0 Cinnarizine
+ DL-phenylalanine (2 g); 6. Cinnarizine/,6CD inclusion compound; 6. Cinnarizine/,6CD
inclusion compound + DL-phenylalanine (2 g).

amount is consequently rapidly absorbed.

In the mucus, practically all diapezam is displaced by lipids from the complex,
leading to a free fraction equal to the total amount of diazepam, and consequently
to a high driving force for the absorption. When large amounts of complexed drug
are administered, the displacement may result in a free drug concentration above
saturation.
To determine whether the mechanism described above is also valid for j3CD
complexes with higher complex stability constants, the authors carried out a pilot
study with naproxen (stability constant 2146 M-1 ) microenemas, using four volun-
teers. The absorption of naproxen is scarcely decreased by the complexation. This
result indicates that a considerable displacement ability must exist in the rectum,
because the stability constant is high and the amount of drug to be displaced is
large.
The absorption of CD both in free and in complexed form is negligible. The
influence of CDs on noninvasive administration is, therefore, restricted to the
invasion phase.
It is an open question how far CDs - especially easily soluble CD derivatives
- can change the permeability of membrane tissues. DIMEB was found to cause
PHARMACOKINETICS AND BIOPHARMACEUTICS 113

some modifications of the gastrointestinal mucosa at high concentrations due to the

removal of membrane components such as cholesterol, phospholipids or proteins.
After dissociation of the complex, CD itself may therefore alter the lipid barrier of
the absorption site, which may possibly facilitate drug absorption [16].
Possible influences of CDs on the permeability of the absorption membrane are
also discussed in Sections 6.3, 8.4 and 8.5.
Nonparenteral administration of a CD-complexed drug does not give rise to
the expectation of any significant modification in its distribution and elimination,
because CDs are scarcely absorbed. In i.v. administration of CD-containing for-
mulations, however, an influence on drug distribution and elimination is not im-
probable. One cannot rule out that the rate of metabolism of a drug is modified
by influencing an existing first-pass effect by higher peak plasma levels on the
administration of a complex. These effects can influence the incidence and the
duration of the therapeutic effect or side effects. Only that fraction of the drug can
exert therapeutic effects and side effects which is not included in the CD cavity.
According to Frijlink, after i.v. administration of drug/CD complexes, the amount
of drug that remains complexed in the circulation depends on:
- the complex stability constant of the drug;
- the affinity constant of the drug with plasma protein;
- displacement of drug from the CD complex by endogenous lipids (e.g. choles-
terol);
- the administered dose; and
- the animal used in the experiments [17].
When drugs which become highly bound to plasma protein are complexed with
CDs and added to plasma, only small amounts of drugs will remain complexed,
depending on the complex stability constant of the drug with the CD. A competition
between CD and proteins for the drug, and a simultaneous competition between
drug and cholesterol for the CD, diminish the fraction of the drug that remains
complexed by the CD.
Complexation of naproxen with HP,BCD does not change the disposition of
the drug in the body after i.v. administration to rats. As a result of the relatively
low complex stability constant, the high plasma protein affinity of the drug and
displacement of drug from the CD complex by cholesterol, it is very likely that
practically no naproxen remains complexed after administration [18].
When flurbiprofen is complexed with HP,BCD (stability constant 12500 M-1)
slight changes in the disposition of the drug occur. The drug concentrations
in organs with a relatively high blood flow, such as liver, kidney, spleen and
brain, are increased 10 min after injection, probably as a result of decreased
plasma protein binding. CDs are obviously more efficient carriers of the drug
114 CHAPTER 6

to biological membranes than plasma proteins. The drug concentrations in the

tissues 60 min after administration are not changed by complexation, except for
the brain concentration. Obviously, the HP;3CD concentration has decreased so far
by that time that it cannot exert any effect any longer, and the normal equilibrium
between circulation and tissue concentration of the drug will reestablish itself. The
association constant with plasma proteins of fiurbiprofen is 5.32 x 105 M-1. The
complex stability constant of cholesterol with HP;3CD is 1.9 x 104 M-1, which is
higher than for most drugs [18].
Some controversial results were obtained by Shirakura et al. [19]. The sleep-
ing times provoked by hexobarbital, pentobarbital, phenobarbital, and thiopental
(215.3 p,mollkg) in mice are significantly shortened upon i.v. administration with
simultaneous i.v. application of ;3CD. The sleeping lags are not affected. The
authors explain this in terms of a decrease in the distribution of the barbiturates to
the brain, at least partly as a result of complex formation with ;3CD. This difference
might be due to differences in protein binding of the drugs. Barbiturates have a
relatively low affinity for plasma proteins and a high partition into tissues. The free
fraction of barbiturates is relatively high (40-60%). Therefore, the drug fraction
that is complexed by CDs will be relatively high and will originate mostly from
the nonprotein-bound fraction. Since the affinity of the complex for membranes in
compartments such as the brain and the liver is likely to be lower than that of the
free drug, complexation results in decreased tissue concentrations in the liver and
brain.
It is obvious that the pharmacokinetics of a drug cannot only be modified by
CDs if the CD-complexed drug is administered, but also when a mixture of the
drug and CD is administered simultaneously. Prerequisites are that both the drug
and CD are rapidly dissolved, the complex stability constant is not too low, and the
dilution effect after the administration is not too large.
Less frequently used CD derivatives are also reported to result in higher bioavail-
abilities.
Phenytoin was administered perorally to dogs in the form of its soluble ;3CD
polymer complex. The AUC of the complex was about twice as great as that from
phenytoin alone, for up to 24 h post administration. The enhanced absorption of
the drug from the complex is probably a consequence of the rapid dissolution and
dissociation of the complex [20].
Yoshikawa developed a bifunctional delivery system with the participation of
an aqueous soluble ;3CD polymer for a drug transport into the lymphatic system
[21]. It consists of a combination of a soluble drug/ ;3CD polymer complex as a
lymphotropic carrier and a micelle-forming surfactant. On administering carmofur
into the large intestine of mice, no lymphotropic selectivity is observed with ;3CD
PHARMACOKINETICS AND BIOPHARMACEUTICS 115

Table 6-11. Ratio of carmofur concentration in the lymph rela-

tive to plasma 2.5 h after administration.

Carrier Lymph/plasma
cone. ratio

1.0
(3CD polymer 1.1
Surfactant (BL9-EX) 1.1
(3CD polymer + surfactant 2.5

polymer or with a surfactant alone; using them in combination, however, gives

double the lymph level, as compared to the plasma concentration (Table 6-II) [22].
It is supposed that the polymer inclusion compound is absorbed from the lumen
of the large intestine by mixed micelles as absorption promoter; the complex may
then be transferred into the lymph vessel selectively due to the large size of its
molecule.
On the other hand, after i.p. administration to rats the carmofur/,BCD polymer
complex without mixed micelles increased the selective transfer of carmofur into
the lymphatics. In the abdominal cavity there is no mucosal barrier which needs a
mixed micelle system for absorption [22].
Peroral administration of maltosyl (G2)-,BCD complexes and ,BCD complexes
of tolbutamide to rabbits resulted in the plasma peaks at 2 and 2.5 h, respectively;
in both cases this is faster than tolbutamide alone (Figure 6-7). This initial increase
in drug absorption might be due to the high dissolution rates of both complexes
[23].

6.2. Enhancement of the Pharmacological Effects

The administration of ,BCD inclusion compounds can influence the intensity and
duration of therapeutic effects in different ways. Increased blood levels of a drug
are normally manifested in enhanced biological effects. In some cases, only the
solubilization of a drug by CDs enables the onset of a therapeutic effect. Increased
plasma levels with a steep Cmax value include the risk of side effects, particularly
with highly active drugs. Otherwise, administration of a CD complex with a
large stability constant or with insoluble diethyl- or triethyl-,BCD results in a small
amount of dissolved, dissociated free drug. Only the free drug can exert the
therapeutic effect. A sustained release effect or even a diminished effect can
116 CHAPTER 6

E
~ 100
c
a
-a
•...
c
OJ
u 50
c
a
u
a
E
1II
a
Q.

a ~~~--'---~--~------T-------~--
o 2 3 6 h 8
time
Fig. 6-7. Plasma levels of tolbutamide following peroral administration CD complexes to rab-
bits .• Tolbutamide; • Tolbutamide/,6CD complex; 0 Tolbutamide/maltosyl-,6CD complex;
n=3.

therefore be observed.
A number of more intensive responses after administration of CD complexes
are known. Increased excreted volumes of urine were examined after peroral
administration of ,CD-containing formulations of furosemide to humans [24]. The
following formulations - containing 40 mg furosemide each - were administered
in a crossover design:
A: micronized furosemide;
B: mixture of ,CD and furosemide (11.3%)
C: ,CD coprecipitate (11.3% furosemide);
0: ,CD freeze-dried product (20.4% furosemide).
All f'CD-containing formulations show increased excreted volumes of urine
(Table 6-III). When administering pure furosemide the lowest volumes of excreted
urine are observed during the first 3 h. The following mean relative bioavailabilities
are obtained: A 100%, B 145%, C 155%, D 161 %. There are no significant
differences between the CD-containing samples B, C, and D. The strong effect of
,CD in the mixture is noticeable [24].
Greater increases in urinary volumes in rats are obtained with the administration
of ,BCD inclusion compound of spironolactone than with spironolactone alone [25].
PHARMACOKINETICS AND BIOPHARMACEUTICS 117

Table 6-III. Urinary excretion after peroral administration of ,CD-containing

furosemide formulations in humans.

Excreted urine volume (ml) after

0.5 h 1.5 h 3h 24 h

Furosemide 100 783 1420 2506

Mixture (ll.3% furosemide) 157 1084 1925 2892
Coprecipitate (11.3%) 183 1106 1767 2586
Freeze-dried product (20.4%) 192 1102 1664 2724

The biological effects of cholecalciferol [26] and menadione [27] are enhanced
in rats and chickens if the compounds are given as the ,BCD inclusion compound.
The efficacy of vitamin K2 is enhanced after peroral administration of the DIMEB
inclusion compound to rabbits [28].
The peroral administration of five barbiturate/ ,BCD complexes to mice results in
50% lower effective doses (EDso) than the intact drug. Figure 6-8 illustrates a re-
lationship between the stability constants of the complexes, the solubilities and the
EDso. The most remarkable reduction of EDso is observed after application of the
phenobarbital complex. Phenobarbital forms the most stable complex and shows a
great enhancement of solubility. With the exception of barbital, complexation also
significantly elongates the sleeping time [29].
The poorly soluble dipyridamole forms an inclusion compound with ,BCD which
is more soluble and more bioavailable than the uncomplexed compound. The in-
clusion compound, dipyridamole alone, and dipyridamole dispersed in lactose,
respectively, are administered perorally to conscious dogs, rabbits, and mice.
Dipyridamole/ ,BCD causes a stronger and prompter coronary and carotid vasodi-
latation in dogs, at doses which weakly influence the systemic arterial pressure and
heart rate. Studies on tail bleeding time have confirmed that dipyridamole/ ,BCD
complex is more active than dipyridamole when given perorally to mice [30].
The accelerated absorption, and concomitant improved headache relief of ,BCD-
complexed piroxicam (20 mg drug per dose) are illustrated in Table 6-IV and
Figure 6-9 [31].
Benexate/,BCD inhibits ulcers induced by HCL-ethanol ingestion, whereas
benexate alone and benexate-CD mixture have no effect [32].
Ninety patients with inoperable carcinoma in the terminal stages and 12 pa-
tients in serious conditions with other tumour types were given benzaldehyde
as the ,BCD inclusion compound, either perorally or rectally, at a daily dose of
10 mg/kg, divided into four doses. Fifty-seven of the patients treated were eval-
118 CHAPTER 6

EDSOcompl.

EDSO free

0.95

0.90

0,85

0.80

0.75 ..1-----r---.---.----,---.---
2 4 6 8 Scompl.

Sfree

Fig. 6-8. Correlation between enhancement of solubility (Scomp!. / Sfree) and enhancement of
hypnotic activity (= reduction of EDso) by CD complexation of barbiturates.

QJ 3.0
L-

a
u
III 2.5
>.
.•...
III 2.0
C
.•...
QJ

c 1.5
c
CI
0.
1.0
c
CI
QJ
0.5
r-
C
0
0 15 30 60 120 min 180
time

Fig. 6-9. Pain intensity: effect of piroxicam and piroxicamJ,BCD as a function of time. 0

piroxicamJ,BCD; 0 piroxicam capsule; 6. piroxicam solution.

PHARMACOKINETICS AND BIOPHARMACEUTICS 119

Table 6-IV. Mean plasma levels (mg/L) of piroxicam and

piroxicaml,BCD in 36 patients treated for headache .

. Time after Piroxicaml ,BCD Piroxicam Piroxicam

administration soluble tablet capsule
(min)

30 2.10 1.68 1.l9

60 2.21 1.91 1.48
120 2.24 2.02 1.51
180 2.20 2.01 1.50

uated. Nineteen of the patients responded completely and 10 patients partially.

For all responding patients, longer response durations were associated with longer
treatment periods with the complex. Toxic effects, including haematologic or bio-
chemical disturbances, were not seen during long-term successive administration
of benzaldehyde/ ,BCD inclusion complex [33].
Other examples report the enhancement of the antiinflammatory effect of in-
domethacin as the ,BCD inclusion compound [34], and a potentiation of the hypo-
glycaemic effect of acetohexamide as the ,BCD complex in rabbits [35].
Enhanced therapeutic effects are also observed when using other administration
routes.
The vasoconstrictor activity of beclomethasone diproprionate is increased on
complexation with ,CD. In addition, the EDso value is lowered by complexation
(EDso = 9.0 x 10-3 for the pure drug, and 2.7 x 10-3 for the ,CD inclusion
compound) [36]. This suggests an improvement in the percutaneous absorption of
beclomethasone diproprionate from an hydrophilic ointment in man (Figure 6-10).
The analgesic effect of morphine - studied on rats by the hot plate method - is
significantly enhanced by DIMEB. On account of the low solubility of morphine
base, it could be injected in suspension only intraperitoneally. Application of
DIMEB reduces the EDso value to 46-58% of morphine, i.e. that analgesic effect
is doubled. It is particularly important that morphine base can be administered i.v.
and s.c. with DIMEB. In this form the activity is fourfold as compared to morphine
hydrochloride [37].
Several anticonvulsant test models were used to evaluate a preparation of car-
bamazepine and HP,BCD. Carbamazepine, when solubilized in this manner, was
found to exert potent anticonvulsant effects. The onset of the action is rapid and
consistent with almost instantaneous in vivo complex dissociation [38].
120 CHAPTER 6

100

>
~ SO
~
o
u
~
Iii
c
o
u
o
Ul
o
> a ~~ __ ~~ __ L- -L ~

concentration of beclomethasone dipropionate

Fig. 6-10. Vasoconstrictor activities of hydrophilic ointments containing beclomethasone

dipropionate (.) and its ,CD complex (0).

6.3. Reduction of Side Effects

Generally, both the desired pharmacological effects and the unwanted side effects
are elicited only by the uncomplexed drug molecules. A complexed drug may be
less toxic than the free one - e.g. in case of local irritation - or more toxic: the
solubility and bioavailability of a poorly soluble toxic substance are increased by
CD complexation. The value of the stability constant of the complex determines
the complexed-to-uncomplexed drug ratio.
The alleviation of local or systemic side effects in the presence of CDs has
been described. Reduced injuries of GI mucosa, of the skin, the eye, the muscular
tissue or reduced erythrocyte haemolysis are examples. A systematically effective
detoxification mechanism by CDs has also been described.
The local irritating effect implies the direct contact of the irritating substance with
the membrane tissue. Crystals of sparingly soluble drugs, e.g. antiinflammatory
nonsteroidal substances, can remain in contact with the gastric mucosa for a longer
period of time; this results in dangerously high local drug concentrations which
can provoke an ulcer.
Drugs can be associated with constituents of tissues and can sequester cell
membrane components. This is observed particularly with amphiphatic drugs
which are able to form micelles and thus include lipophilic tissue constituents into
the micelles. The encapsulation of a drug in the CD cavity can, depending upon
PHARMACOKINETICS AND BIOPHARMACEUTICS 121

ml
6

5 / •..•...
/ .•....•...

4 / .
/ .•...
I
3 I
I
2 I
/
""...------,
.•...•..
O~--,-~<----·----·-,_·--·----·~-·----·----·~·--~·-~~---
2 3 week 4
time
Fig. 6-11. Gastrointestinal microbleeding provoked by piroxicam (- - - -), piroxicaml ,BCD
complex (-) and placebo (_._._) in human.

the CD concentration and the complex stability constant, restrict the direct contact
of the drug with the cell membrane.
Indomethacin, flurbiprofen, biphenylacetic acid, naproxen, and phenylbutazone
are examples where GI mucosa irritating effects are reduced by CD complexa-
tion. The ulcer inducing effect of indomethacin can be reduced significantly by
formation of a CD inclusion complex. A 5 mg/kg/day peroral treatment of rats
with indomethacin or with indomethacin/CD complex (40.3 mg complex, equiva-
lent to 5 mg indomethacin) for 28 days results in a considerable reduction of the
ulcer-inducing effect of indomethacin by the complex [39].
A similar observation was published for phenylbutazone. Rats were treated
perorally with a single 100 mg/kg dose or with an equivalent amount of phenyl-
butazone/ j3CD complex and sacrificed 18 h later. The degree of injury with free
phenylbutazone is about four times larger than with the complexed drug [40].
Figure 6-11 illustrates the gastrointestinal microbleeding (= faecal blood loss)
provoked by piroxicam, piroxicaml j3CD complex and placebo. As can be seen,
the CD complexation strongly reduces the stomach irritating effect of piroxicam
[41].
The toxicity of the j3CD inclusion compound with the neoplasm inhibitor
N1, N2-bis(2-tetrahydrofuryl)-5-fluorouracil is lower than that of the parent flu-
orouracil compound. Peroral administration of the inclusion compound (150-
600 mg/kg) prolongs the life span of mice afflicted with Ehrlich carcinoma. The
effectiveness is similar to that of the parent compound [42].
A decrease in the irritant power of 2-(2-fluoro-4-biphenyl)propionic acid, a
122 CHAPTER 6

20

-20

-40

-60

-80

-100

-120

-30 -15 0 15 30 60 90 120 150 . 180

mm
time

Fig. 6-12. The effect of intravenous HP;3CD administration on the plasma concentration of
free cholesterol. The changes in cholesterol level (mean ± SE) compared with the first sample
(time = -30 min) are plotted against time. x saline (n = 8); • HP;3CD 100 mg/kg (n = 5); 0
HP;3CD 200 mg/kg (n = 4).

prostaglandin synthesis inhibitor, on the eye has been reported on inclusion in

j3CD or ,CD [43].
Intramuscular injections of tiamulin - an important antibiotic for domestic an-
imals - causes local irritations and haemorrhagic areas. The irritative effects
exerted by the ,CD complex on the M. vastus lateralis of rabbits are milder than
after tiamulin alone [44].
HEj3CD, HPj3CD, and glucosyl-CDs are more effective in reducing the local
toxicity induced by drugs as compared to natural CDs, owing to their highly
hydrophilic nature. The hydrophilic complexes have a poor affinity for the muscle
tissue membrane [16].
CDs protect erythrocytes from haemolysis induced by a variety of drugs. The
induced haemolysis with chlorpromazine is prevented in isotonic solution depend-
ing on the magnitude of the stability constant of chlorpromazine/CD complexes
(j3-t,-taCD). From the observation of the chlorpromazine uptake into erythro-
PHARMACOKINETICS AND BIOPHARMACEUTICS 123

Capillary
wall
Blood Interstitial fluid
I
I
I Llpoprolelns
I
Lipoproteins !:%;
I
/

-,
.I- Co+Choleslerol
I
II +CD
I
I
I ) cell membran
I
I
CD-Cholesterol I Co-Choleslerol

complex ~ complex
I
I
I
I
I
I
I
I
I
•
Fig. 6-13. Suggested model for the plasma cholesterol decreasing effect of CDs.

cytes and changes in surface activity of chlorpromazine, the protective effects of

CDs in vitro appear to be due to the decrease in effective haemolytic concentra-
tions of chlorpromazine through inclusion complex formation rather than the direct
interaction of CDs with the erythrocyte membrane [45].
The haemolytic and erythrocyte shape change inducing effects of the antide-
pressant imipramine can be prevented by CDs, the most effective being ,BCD. The
affinity of complexed drug molecules for the cell membrane is strongly decreased
by the CDs [46].
Platelets which were collected after peroral administration of dipyridamole/ ,BCD
inclusion compounds from treated rabbits appear to be protected from sodium
adenosinediphosphate-induced aggregation in vitro more effectively and rapidly
by the complex than by dipyridamole alone [30].
A number of substances can cause phototoxic and photoallergic responses in
patients being treated with prolonged and high doses of such drugs. These effects
can be attributed mainly to the toxic photoproducts whose formation is decreased
by CD inclusion.
,BCD and DIMEB suppress benoxaprofen-photosensitized haemolysis, where
the inhibitory effect of DIMEB is larger than that of ,BCD. This order was well
correlated with the magnitude of the stability constants ofthe complexes [47].
124 CHAPTER 6

The haemolytic activity of protripty line solutions increases with irradiation time,
and protriptyline solutions irradiated under anaerobic conditions show stronger
haemolysis than those irradiated under aerobic conditions. Since ,BCDs themselves
have little protective effect on haemolysis under the experimental conditions, the
inhibitory effect of ,BCD may be mainly due to the alteration in the photochemical
reactivity of protriptyline through inclusion complexation rather than to the direct
interaction of protripty line with ,BCDs [48].
Inclusion into CDs can reduce photosensitized damage to the skin. The topical
administration of imidazoles may give undesirable side effects, such as irritation
or allergic reactions. The skin irritation induced by prochlorperazine could be
alleviated by CD complexation of the drug [49].
,BCDs significantly alleviated the phototoxic irritating reactions of chlorpro-
mazine in the order of HP,BCD < ,BCD < DIMEB. This order was well correlated
with the magnitude of the stability constants of the inclusion complexes. The per-
cutaneous absorption of chlorpromazine was inhibited by CDs in the same order.
The photoreaction pathway of chlorpromazine in the skin was changed by ,BCDs,
i.e. less toxic promazine is predominantly produced in the presence of ,BCDs
(DIMEB > ,BCD 2:' HP,BCD) [50].
The administration of 'empty' CD molecules to the blood provides the op-
portunity for the formation of a complex with constituents of the blood serum.
Complexation of a drug with CDs can be regarded as competing with the drug
albumin interaction. If undissociated complex circulates in the blood, a higher
drug level can be tolerated, which means that toxicity can be reduced.
This detoxification mechanism was successfully applied by Perrin et al. The
extraction of barbiturates from rats by intraperitoneal dialysis was about three times
faster when the dialysing solution contained ,BCD [51].
Pitha and Szente studied the relief of A-hypervitaminosis by parenteral ap-
plication of DIMEB. About 50 f-Lg/kg of the retinoid proved to be sufficient to
prevent avitaminosis. At a hypervitaminotic level of about a one-thousand times
higher dose, retinoids inhibit the growth of carcinogen-induced cancers in epithelial
cells. At such high concentrations, however, retinoids are toxic. On administer-
ing 100 rng/kg retinoic acid intraperitoneally to mice, only 37% survived, while
69% survived and recovered from hypervitaminosis when DIMEB was also in-
jected. The level of the free vitamin was probably decreased by complexation with
DIMEB, resulting in a reduced toxicity [52].
Intravenous administration of HP,BCD to rats leads to a transient decrease in
plasma cholesterol levels (Figure 6-12) [53]. In blood, high concentrations of
cholesterol are available which form a complex with the CD derivative. This
complex can be transported rapidly from the intravascular to the extravascular
PHARMACOKINETICS AND BIOPHARMACEUTICS 125

compartment (Figure 6-13). The increased transport rate increases the apparent
volume of distribution for cholesterol and explains the decrease in plasma choles-
terollevels after CD injection [53].

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