Griseofulvin: the effect of fat intake on gastrointestinal absorption
Answers
of superficial fungus infections in man is well
established. Our pharmacologic knowledge of this
compound, however, lags behind our clinical
knowledge. The pharmacology of griseofulvin administered
orally to animals has been studied by
the Glaxo Laboratories group in England (1, 2, 3).
The bulk of griseofulvin given orally is excreted
from the gastrointestinal tract apparently unchanged
(2). Absorption occurs from the small intestine,
probably the duodenum. Declining blood
griseofulvin levels at a time when substantial
amounts of the drug are still present throughout
the gut seem to indicate a self-limiting absorptive
process in the rat (2) and the cat (3). No griseofulvin
could be detected in the blood of rats 12
hours following an oral dose of 10 mg/rat, despite
recovery of 69 per cent of the administered material
from the gut at that time (2).
Variations of the amount of griseofulvin absorbed
in different individuals might be of clinical
importance if the amount were insufficient to
eradicate the infection. Such variation seemed
likely with a drug whose absorption is known to
be limited in animals. Our initial purpose, therefore,
was to measure the degree of variation of
serum griseofulvin levels following a standardized
oral test dose, and to compare these with values
obtained in individuals clinically unresponsive to
average therapeutic doses of griseofulvin. Simultaneous
determinations of the in vitro sensitivity
to griseofulvin of the fungi isolated from these
same patients were performed. Thus, clinical unresponsiveness
based on actual resistance of the
organism could be detected. Such resistance has
been reported by Fisher et at. (4) and by
Miehaelides et at. (5).
A means of increasing the absorption of
* From the Department of Dermatology, University
of Miami Medical School, Miami, Florida.
t Part of this work was performed while the
author was a Public Health Research Fellow of
the National Cancer Institute.
Additional support for this project included
grants from the National Institutes of Health
and U. S. Army Contract *'DA-49-007-MD-31.
Presented at the twenty-second Annual Meeting
of the Society for Investigative Dermatology,
Inc., New York, N. Y., June 29, 1961.
griseofulvin seemed important, particularly in
those individuals who might be unresponsive because
of inadequate absorption. The solubility of
griseofulvin is limited largely to organic solvents
such as dimethylformamide and diethylether. The
absorption of Vitamin A, another fat-soluble
compound, is known to be increased by feeding
with lipid materials (6). It was predicted by
analogy that the absorption of griseofulvin could
be increased by administration in conjunction with
a meal high in fat content.
MATEEJAL5 AND METHODS
Serum griseofulvin levels were assayed by the
spectrophotofluorometric method of Bedford,
Child and Tomich (1) as adapted by Weinstein
and Blaok (7). The assay is based on maximum
fluorescence of griseofulvin at 450 mp when excited
by an incident beam of 295 mp. It is a very
sensitive method, capable of detectiog submicrogram
quantities of griseofulvin.
The oral test dose was 1.0 gm. of griseofulvin
administered in the fasting state. Blood was
obtained by venipuncture at zero, 4, 8 and 24
hours following the test dose. The blood was
clotted at room temperature, rimmed and centrifuged
at 3,000 rpm for 20 minutes; the serum
was pipetted off and the griseofulvio extracted
and estimated.
It is worthy of re-emphasis that contamination
by interfering fluorescent substances is an everpresent
danger. We have used a separate set of
acid-washed and ethanol-rinsed glassware
throughout the experiments. Disposable plastic
syringes (Tomac) found to be free of contaminants
were used for venipuncture.
Thirty-seven individuals were included io the
control series. Repetitive estimations were performed
io several of these to assure the reproducibility
of the test. All other medications were
withheld during the period of testing. Aspirin,
for example, may interfere with the assay, as
Marvel (8) has indicated.
Ten individuals following the standard test
were again given 1.0 gm. of griseofulvin, but after
a high fat breakfast (bacon, eggs, cream and
butter). The test was also run following high
protein, high carbohydrate and low fat meals to
rule out a nonspecific effect of other non-fatty
foods. In addition, serum griseofulvin levels were