University of Groningen
Absorption, distribution, metabolism, and excretion of the cutaneous penetration
enhancer Azone
Wiechers, Johann Wilhelm
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Publication date:
1989
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Wiechers, J. W. (1989). Absorption, distribution, metabolism, and excretion of the cutaneous penetration
enhancer Azone s.n.
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SI]HMARY
Azone@ (1-dodecylazacycloheptan-2-one;
Nelson Research,
Irvine,
CA, USA)
has been shown to be of
great
value
in enhancing
the
flux
of drugs
through
both
animal
and human skin
ín-vitro.
This
pÍoperty
opens new
possibilities
for dermal and transdermal
drug delivery
of compounds that
are
normally
absorbed
by
the
skin
in
insufficÍent
amouncs.
However,
prior
to human use in daÍ1y clinical
practice,
adequate information
is
requíred
concerning
the fate of Azone in the body. This thesis
describes
the
absorption,
distribution,
uretabolisn,
and
elimination
of
this
penetration
enhancer.
A twofold
approach
was choosen.
On the one hand,
clinical
studies
were
performed
in
which
radioactive
Azone was applied
to
the
forearm
of
volunteers.
The absorption,
distribution
in the skin,
and excretion
of
Azone and Azone-derived
material
were studied,
in combination
with
the
compound's metabolic
profile
in the major excretion
nedia.
On the other
hand, metabolic
studies
in warious
animal species,
isolated
livers
and
(sub) ce'l IuIar
in
I i ver
frac L i ons were performed
and compared. to
thc
human ín-v-ivo metabolism.
Prior
to the presentation
of the experimental
resulcs,
detailed
background information
í.s prowided
on the skin as a barrier
ín relation
to
percutaneous
absorption
of drugs (Chapter 2). Subsequently,
the reader
is
familiarized
with
Azone's
pharmaceutical
and analytical
aspecrs
(Chapter 3).
Chapters
4 and 5 describe
che percutaneous
absorption
of Azone when
dosed as the neat liquid,
its
skin distribution,
and disposicion
in the
ttC-Azone, labelLed in the a-posi.tion
excreta.
in Lhe side-chain,
was
dosed as no method was avaílable
to foll.ow the unlabeJ_led compound. ic
could
be demonstrated
that
the percutaneous
absorption
of the compound
was very
low: Less than 0.5t either
after
a single
dose for 4 h under
non-occlusive
condicions,
or a single
dose for
12 h under occiusive
conditions.
Accumulation
of Azone in the stratum
corneum did not occur.
of radioactiwity
Elimination
was complete wichin
120 h and took place
(>95t)
predominantly
through
the
urine.
Metabolic
profiling
of
rhe
l-atter
revealed
vircually
complete extensive
metabolism
of Azone to at
least
three very polar metabolites.
The percutaneous
absorption
of I'qC-Azone, incorporated
in a therapeutic
at a concentration
formulation
of l. 6t, also containing
propylene
g1yco1
(0.05t).
and the therapeutic
agent triamcinolone
acetonide
was studied
multiple
dermaL
following
application
under
occlusive
conditions
(Chapter 6). Absorption
of Azone was found to be hÍ.gher ar 3.5t,
but rhe
amounts were approximately
absoiute
the same as seen i-n the single
dose
study
uncler occLusive
conciLlons.
indicacing
Lhat rhe flux
c.rf Azone
human skin
is e.zen lower when dosed in a therapeutic
through
formulaplateaued
within
tion.
Absorption
3 days. Higher trewels of radioaccivity
in the stratum corneum following
could be retriewed
multiple
dosing when
single
dosing,
but
cornpared to
agai-n, lhere
were no indications
of
parameters were itot affected
accr.rmulation ln the skin" A11 other kinetic
formrrlation.
by the therapeutic
a new rnethod to establish
Chapter
7 describes
cutaneous
metabolÍsm
of
appl íed drugs,.makíng use of Lhe ouLward migraLion of subsLantopically
t*C-Azone-derÍveci
the skirr.
ces through
radioactir-ity
appeared to be
present
in
the
stratum
eorneum as the unchanged
compound only.
Yet,
another
compound that
Cyoctol,
is being tested
t-or dermal application,
148
rÍne, CA, USA)
Êlux of drugs
rty opens nert
lonpounds that
nts. However,
.nfornatlon
ls
rsls descrlbes
:lon of this
. gtudies were
re forearn of
, êxcretlon of
tÍon wi.th the
0n the other
ed IÍvers and
ryared to the
etaÍled back,n relation
to
y, the reader
tlcal
aspects
rf Azone when
rsltion ln the
de-chain, was
I cornpound. It
the conpound
Êor 4 h under
il,er occlusive
ild not occur.
nd took place
tltng
of the
f Azone to at
shoned considerabLe cutaneous rnetabollsm.
performed
Chapters 8 and 9 describe
the metabolic
studles
in aninal
lsolated
liver,
species,
and (sub)cellular
llver
rnaterlal.
Azone
appeared to be metabollzed
to different
compounds Ín hamster,
rat,
monkey, and man, the polarlty
of the bulk of their
respectlve
metabolites
lncreaslng
1n thls order. In all specles, the exeretÍon
rras nainly
by the kidneys.
As raË metabolí-tes most closely
corresponded
the human
products,
biotransformation
this anlnal sas selected
for addltlonal
invivo and i-n-vitro
studies.
It could be demonstrated that the transposition of the radioactive
isotope from the sÍde-chain
to the ring did not
proflles,
affect
the metabollc
suggesting
that
total
cleavage of the
side-chain
or ring-openÍng
rith
subsequent rernoval of the carboxyl
functlons
did not take place. Likewise,
intravenous
and oral ad,nlnistratÍon of Azone resulted
profile,
in the sane netabollc
suggesting
the
gastro-intestinal
tract
to be not lnvolved ln the metabolisn
of Azone.
perfuslon
Subsequently,
both rat llver
and rat hepatocyte
experinents
demonstrated thls organ to be capable of bÍoconverting
Azone to the same
rnetabol.ltes as encountered ln the in-vivo
profile,
via the fornatlon
of
transÍ.ent,
relatÍve
non-polar netabolites
that rrere aLso produced by the
human hêpatocytes.
Rat and human microsones
nere
also
capable
of
producing these non-polar rnetabolites
but falled
to generate the in-vivo
products of elther species.
Chapter 10 describes
the influence
of Azone on the percutaneous
absorptlon
of triancinolone
acetonide
and provldes
the flrst
evidence
that
Azone acts as a penetration
erihancet in-vívo
in human skÍn when dosed in
a therapeutlc
formulatlon.
EnhancemenË factors
nere
1nËroduced
to
quantitate
the lnfluence
of Azone. Ttre enhancement factor
was found to
be 3,2 for
singl-e dosing of Azone, whereas multiple
dosing
further
increased the extent of absorption by a factor 2.1, resultlng
1n a total
enhancernent factor of 6.8.
presented
ïhe results
in this
thesis
indicate
that
due to lts
low
percutaneous
absorption,
the body burden of Azone ls low. Accr:mul.ation
does not take place in the skin,
nor at any other site
of the body.
is complete, rapid (sithin
Excretion
3-5 days), and predomlnantly
lnto
the urine
in which it is present as polar netabolltes.
Tlrese conbined
results
suggest Azone to be safe for human use.
e therapeutlc
rpylene glycol
, was studled
e condltlons
3.5t, but the
re single dose
llu:r of Azone
utlc fornularadloactlvlty
.e dosing when
ndicatlons
of
r not affected
uetabolisn of
rn of substanrpeared to be
rd on1y. Yet,
application,
L49