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Antimicrobial Agents and Chemotherapy, January 1999, p. 148-151, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Penetration of Oral Fluconazole into
Gynecological Tissues
Hiroshige
Mikamo,*
Kyoko
Kawazoe,
Yasumasa
Sato,
Koji
Izumi,
Toshiya
Ito,
Kunihiko
Ito, and
Teruhiko
Tamaya
Department of Obstetrics and Gynecology,
School of Medicine, Gifu University, Gifu, Japan
Received 17 November 1997/Returned for modification 2 May
1998/Accepted 20 October 1998
 |
ABSTRACT |
Penetration of fluconazole into female genital tissues was
examined. Fluconazole was administered orally at a dose of 150 mg to
patients undergoing total abdominal hysterectomy 1 to 151 h prior
to surgery. During surgery, blood, uterus, ovary, and oviduct were
sampled. Fluconazole concentrations in each tissue were determined by
high-performance liquid chromatography. The peak concentrations in
serum reached approximately 6.1 µg/ml 1.0 h after a drip
infusion was begun. At each time after the infusion, the concentrations
in portio vaginalis, cervix uteri, myometrium, endometrium, ovary, and
oviduct were higher than those in the serum: the peaks in the tissues
ranged from 6.4 to 9.5 µg/g around 1.0 h after the drip infusion
was begun. Thus, the levels of penentration of fluconazole into
gynecological tissues appeared to be similar to or slightly above those
in serum samples. Fluconazole can rapidly penetrate from plasma into
the female genital organs, supporting high efficacy of fluconazole
against fungal infections in the field of gynecology.
| |
INTRODUCTION |
Vaginal candidiasis is an infection
caused by Candida albicans or related fungi. The fungi
isolated from the vaginas of patients with candidiasis include C. albicans (80 to 90% of patients), Candida glabrata,
and Candida tropicalis.
The usual transvaginal treatment of candidiasis can be messy and
displeasing and can include local irritation, burning, and frequency of
micturition. Consequently, complicance with this form of treatment is
poor, as women often stop the treatment as soon as their symptoms
disappear but before eradication of the fungi. The rectum is a carrier
of the fungi, and relapses are common.
Fluconazole is one of the antifungal agents which are effective against
not only systemic fungal infection but vaginal candidiasis; however,
there have been no published data on penetration of oral fluconazole
into gynecological tissues. The concentrations of fluconazole in serum
and gynecological tissues (uterus, ovaries, and oviducts) were
determined to reveal the drug's effective distribution.
| |
MATERIALS AND METHODS |
Drug.
Fluconazole
[
-(2,4-difluorophenyl)--(1H-1,2,4-triazol-1-ylmethyl)-1H-1,2,4-triazole-1-ethanol]
(150 milligrams) was used in this study.
Subjects.
Fifty-seven patients (mean age ± standard
deviation, 54.7 ± 7.5 years; mean weight ± standard
deviation, 54.8 ± 6.4 kg) were chosen for the study. Patients
underwent total abdominal hysterectomy for the treatment of myoma uteri
and other conditions at the Department of Obstetrics and Gynecology,
School of Medicine, Gifu University; Gifu Municipal Hospital; Gihoku
General Hospital; and Gifu Prefectural Gifu Hospital from June 1996 to
March 1997. They agreed to participate in this study. These patients
showed no abnormalities in liver function, having normal levels of
transaminase in serum, or in renal function, having normal levels of
urea nitrogen and creatinine in serum.
Experimental methods. (i) Drug administration.
Before the
operation, 150 mg of fluconazole was orally administered to each patient.
(ii) Sampling method.
After ligation of the uterine artery
on one side in the hysterectomy, blood from the uterine artery on the
other side and cubital venous blood were taken. Also, approximately
1 g each of tissue from the portio vaginalis, cervix uteri,
myometrium, ovary, and oviduct was taken from the normal portions of
the samples immediately after hysterectomy. After centrifugal
separation (1,000 × g, 15 min) of blood samples, the
supernatant was immediately frozen and stored at 
80°C. Each tissue
sample was homogenized, immediately frozen, and stored at 80°C.
(iii) Measurement of drug concentration.
The concentrations
of fluoconazole were measured by a modification of the validated
high-performance liquid chromatography method of John et al.
(13). Each tissue sample was homogenized with a solution
containing 2 ml of 5 M NaOH and 3 ml of ethyl acetate. In accordance
with a cross-matrix compatibility study, serum was used as a control
matrix to prepare a standard curve for tissue samples. Samples prepared
from a rat control liver were assayed against the standard curve for
serum. Levels of accuracy for rat liver were less than 13%. The
percent recovery was 80% for serum.
Chromatographic analysis was performed on an octyldecyl silane-M column
(25 cm [length] by 4.6 mm [inner diameter], 5-µm particles) by
isocratic elution, with a mobile phase of 0.5% ammonium acetate (pH
3.8)-acetonitrile (3:1 [vol/vol]) and UV detection of 260 nm.
Standard curves showed a good linear relationship between peak-height
ratios and fluconazole concentration, with
2
consistently being >0.999. The lower limits of quantitation were
0.4 µg/ml in serum (with 0.5-ml samples) and 0.2 µg/sample in
tissues
(with 0.03- to 0.86-g samples). The between-day (6 days)
precision
values (as percents coefficient of variation) were less
than 3.2%.
(iv) Method of analysis.
Results were analyzed with a
one-compartment first-order-lag-time-first-order-elimination model
(Fig. 1) as follows: C(T) = D*
K01/V/(K01K10)*
[EXP(K10* T) EXP
(K01* T)], where C is
concentration, T is time (in hours), D is dose,
K01 is absorption rate constant,
K10 is elimination rate constant, and EXP is
exponent. The area under the concentration-time curve from 0 h to
T (AUC0-T) was calculated by
the trapezoidal method. Thus, AUC0-
= AUC0-T + CT/kel, where
AUC0- is the area under the concentration-time curve
from 0 h to infinity, CT is the
concentration detected in the plasma at the final time point, and
kel is the elimination rate constant).
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FIG. 1.
Diagram of the one-compartment
first-order-lag-time-first-order-elimination pharmacokinetic model.
See Materials and Methods for an explanation of the abbreviations.
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RESULTS |
The drug concentrations in serum and each genital tissue after
intravenous administration of 150 mg of fluconazole are shown in Table
1 and Fig. 1 and
2.
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FIG. 2.
Drug concentrations in serum and each genital tissue
after oral administration of fluconazole (150 mg).
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|
The maximum concentration of fluconazole in serum was observed to be
6.1 µg/ml at 1.0 h after the drip infusion was begun (Table
2). The peak concentrations in tissues
from the portio vaginalis, cervix uteri, myometrium, endometrium,
ovary, and oviduct ranged from 6.4 to 9.5 µg/g around 1.0 h
after the drip infusion was begun. The levels of penetration of
fluconazole into gynecological tissues appeared to be similar to or
slightly above those in serum samples.
No abnormal symptoms or laboratory findings attributable to fluconazole
were observed in the study.
| |
DISCUSSION |
Systemic fungal infections and superficial fungal infections have
been increasing in recent years, because of the increasing population
of compromised hosts: patients with immune deficiencies due to
diseases, immunosuppression as a result of host reactions to organ
transplants, and neutropenia from cancer or cancer chemotherapy (1-3, 17, 18).
In humans, the volume of distribution approximates that of total body
water (0.8 liter/g). In contrast to the protein binding capacities of
other azole antifungals, that of fluconazole is low (approximately
11%), and therefore most fluconazole circulates as a free form
(4, 5, 10, 20, 22). Alternatively, fluconazole can penetrate
into gynecological tissues in concentrations equivalent to those in
serum, as shown in this study. The peak concentrations in each
gynecological tissue, such as the uterus, ovaries, and oviducts, were
6.4 to 9.5 µg/g around 1.0 h after the drip infusion was begun,
levels which were similar to or slightly above those in serum. The
penetration of fluconazole appears to occur rapidly from serum to each
genital tissue.
Fluconazole inhibited hyphal branching almost totally at concentrations
of 0.2 mg/liter in a morphology study of C. albicans (23). The MICs of fluconazole for pathogenic yeasts fell
within achievable concentrations in serum and gynecological tissues
even around 50 h after drug administration.
The presented penetration of oral fluconazole into gynecological
tissues suggests that fluconazole has a considerable potential for
treatment of not only human systemic fungal infections but also vaginal
candidiasis with excellent activity.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Obstetrics and Gynecology, School of Medicine, Gifu University, 40, Tsukasa-machi, Gifu-City, Gifu 500-8705, Japan.
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Antimicrobial Agents and Chemotherapy, January 1999, p. 148-151, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
