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THE JOURNAL OF INVESTIOATIVE DERMATOLOOY
Copyright 1967 by The Williams & Wilkins Co. Vol. 46, No. S
Printed in U.S.A.
REGIONAL VARIATION IN PERCUTANEOUS PENETRATION
OF 14C CORTISOL IN MANE
ROBERT J. FELDMANN, M.D. AND HOWARD I. MAIBACH, M.D.
Previously we reported hydroeortisone per-
cutaneous penetration rates as estimated by
amounts of radioactivity recovered in the
urine under several experimental circum-
stances but always employing the ventral as-
pect of the human forearm (1). This study
quantitates the effect of regional variation
on percutaneous penetration of hydrocorti-
All subjects were normal male volunteers.
0.06 mg of hydrocortisone with 5 microcuries of
14C activity was dissolved in each 0.1 ml dose,
using acetone as a solvent. The quantity of hy-
drocortisone applied is similar to the application
of a 025 per cent topical preparation. A circular
13 sq cm area was delineated with petrolatum.
The test material was applied with a micropipcttc
and the acetone evaporated by gentle flowing.
The subjects were requested not to wash the area
for one day; the site was not protected. All urine
was collected for 5 days and analyzed for "C by
a method previously described (2). Results are
expressed in per cent of the dose applied. Since
about 75 per cent of an intravenous control-dose
of hydrocortisone appears in urine in man, the
actual penetration of the compound is somewhat
larger than reported here (1).
Measurable absorption occurred through all
regions except the heel.
Table I gives the mean values in each ex-
periment for the total five day excretion and
the rates of excretion in each collection period.
We chose to compare absorption in each anatomic
region with absorption through the ventral as-
pect of forearm (the area most commonly used
and with which we have had the most ex-
perience). Variation between subjects was oh-
This study was supported in part by U.S.P.H.S.
2tTT-AM-5372-01A1, and the Skin Disease Re-
search Foundation. Mr. John Beal of Dome
Chemicals provided the AC hydrocortisone.
Presented at the Twenty-seventh Annual Meet-
ing of The Society for Investigative Dermatology,
Inc., Chicago, Illinois, June 27, 1966.
* From the Division of Dermatology, Depart-
ment of Medicine, University of California School
of Medicine, San Francisco, California 94122.
served; the absorption ratios between ana-
tomic sites in each subject showed a smaller
variation. Subjects served as their own con-
trols for the several areas examined.
Great differences were observed in absorp-
tion through various sites. Fig. 1 illustrates
the ratio of the total excretion for each ana-
tomic site to that of the ventral forearm. This
varied from a trace for the heel (not illus-
trated) to a forty-two fold increase for the
The figures demonstrate the excretion rates
in each time period. The great differences in
penetration required presenting this data in
three graphs with different scales. Fig. 2 shows
the excretion pattern for sites having an ab-
sorption less than that of the ventral aspect of
the forearm: palm, ankle, foot. Fig. 3 shows
this pattern for sites somewhat greater than
that of the ventral aspect of the forearm: dorsal
aspect of the forearm, back, axilla, scalp; Fig.
4 shows this pattern for sites showing a great
increase over the ventral aspect of the fore-
arm: forehead, angle of the jaw and scrotum.
The '4C excretion rate was maximal in the
second twelve hour period except for the foot
and back. The maximum rate for the foot oc-
curred during the third and fourth day. The
highest rate for the back occurred in the sec-
ond day. After the maximum, the excretion
rates in general declined gradually, with meas-
urable excretion in the fifth day.
Several generalizations can be made. Ap-
parent absorption (estimated by amounts in
the urine) is increased in areas where folli-
cles are larger or more numerous (such as the
forehead and scalp) and decreased where the
stratum corneum is thicker (the foot). Our
data suggest, but do not prove, that absorp-
tion takes place transepidermally and through
hair follicles. The increased absorption in
hairy areas may be due partly to structural
differences in the stratum corneum, but the
data suggest that much of the increase is due
182 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Effect of anatomic region on absorption of topical 14 hydrocortisone (Urinary 14C excretion expressed
as % applied dose)
Anatomic region No.
Excretion rate per 24-hours Total exrretion
Collrctino period (days) .
0—1/2 1/2—1 2345
Foot arch (plantar)
* Samples missing: control corrected to 4 day period.
FQRE&R11 (DORSAl.) l.lx
FOOT ARCH (?LAWTAR)U 0.14x
M4KLE (ijstERM..) 0.42's
hz',%4%i%%V,V///////////½i%i7/,l 13.0 a.
HYDIZOCORT%SOME ABSORPTION TOTAL
ECFECT Oc ANPCVOeO%C RC&10t4
Ftc. 1. Hydrocortisone absorption total-effect of anatomic region
to the presence of hair follicles, and probably
occurs through them. In hairy areas, follicular
absorption may be greater than transepider-
These generalizations are not consistent with
onr observations of the palm and scrotnm.
Significant absorption occurred through the
palm, which has a fairly thick stratum cor-
ncum and no hair follicles. The scrotum pro-
vides almost no barrier to hydrocortisone,
quantitating the observation of Smith, Fischer
and Blank (5). Other determining factors
may be present in these regions of obvious
specialization in structure and function.
Tragear (3) concluded that hair follicles do
not increase skin penetration. His experiment
compares disappearance of surface radioactiv-
ity of "P tributyl phosphate when applied
around hair follicles and between hair folli-
cles in the pig. His data show that tributyl
phosphate is absorbed at a rate of 7 per cent
per hour in hairless pig skin areas, while we
find hydrocortisone is absorbed from hairless
human skin areas at a rate of .02 per cent
pcr hour. A compound absorbed this rapidly
(300 times faster than hydrocortisone) may
not show a prominent follicular component.
Others have noted penetration differences in
different body areas. Cronin and Stoughton
(4) have reviewed this data.
PERCUTANEOUS PENETRATION OF '4C CORTISOL IN MAN 183
l-IYNZOCORT ISONE tBSOR%ThOt4
RATES - EFFECT OF N*COMC
Fio. 2. Hydrocortisone absorption rates—effect
of anatomic regions.
ALTES' EFFECT CF AW4T04%C REG%CW&
FIG. 4. Hydrocortisone absorption rates—effect
of anatomic regions.
1. Absorption of bydrocortisone occurs
through all skin regions tested.
2. Absorption is increased in regions with
large or numerous hair follicles. The scalp
absorbed 3.5 times and the forehead 6 times
the quantity of hydroeortisone as the ventral
aspect of the forearm.
3. Absorption is decreased in some regions
of skin having thickened stratum corneum,
e.g. the foot.
4. In seeming contradiction, the palm is far
from impenetrable to hydrocortisone.
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We previously observed clinically that
psoriatic facial lesions respond more readily
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increased hydrocortisone absorption observed
in the present study.
C't05F-UI3IaU102. 5 4
EFFECT OF ACLMOMIC R.E020t43
Fm. 3. Hydrocortisone absorption rates—effect
of anatomic regions.
94 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
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