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Transdermal Absorption of Dimethindene in Man.

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Transdermal Absorption of Dimethindene
Transdermal Absorption of Dimethindene in Man+)
Susanne Radler and Gottfried Blaschke
Institute of PharmaceuticalChemistry, University of Miinster, Hittorfstr. 58-62, D-48149 Miinster, Germany
Received March 7, 1994; revised form received June 20, 1994
Dimethindene and its metabolite N-demethyldimethindene were determined in human urine after dermal administration of dimethindene. The
HPLC-method used was previously described. Data of 8 volunteers are
presented. After 32 h an average of 0.023% of the administered dose of
dimethindene and 0.022% of N-demethyldimethindenewere excreted into
urine. Since also after oral administration of dimethindene only about 1%
of unmetabolised dimethindene is found in urine it can be concluded that a
certain amount of dimethindene is absorbed through the skin after dermal
administration.
Transdermale Absorption des Dimethindens beim Menschen
Dimetinden und sein Metabolit N-Desmethyldimetindenwurden nach dermaler Applikation von Dimetinden in Humanurin bestimmt. Die venvendete HPLC-Methode wurde bereits beschrieben. Daten von 8 Probanden
werden vorgestellt. Nach 32 h wurden im Durchschnitt 0.023% der applizierten Dosis an Dimetinden und 0.022% N-Desmethyldimetinden mit
dem Urin ausgeschieden. Auch nach oraler Gabe wird nur ungeftihr 1%
unmetabolisiertesDimetinden renal ausgeschieden. Die Ergebnisse zeigen,
daB nach dermaler Applikation Dimetinden durch die Haut resorbiert wird.
Dimethindene maleate, (+)-N,N-dimethyl-3-[1-(2-pyridinyI)ethyl]-lHindene-2-ethanamine maleate, is an antihistaminic drug, which is orally
administered (daily doses of only 3-6 mg) as well as dermally (daily doses
of about 1-10 mg). To date transdermal absorption of dimethindene has
only been proven by pharmacological tests, for example by reduction of
the size of erythemas or by attenuating the symptoms of itching after injection of a histamine liberator or histamine'*2).Only for the rat transdermal
absorption of dimethindene was shown with 3H-labelled dimethindene3).
The determination of dimethindene and its metabolite N-demethyldimethindene in urine by HPLC after oral administration to volunteers has been
described4).
ethindene in urine has been described5). However, this
method does not allow the separation of dimethindene and
its metabolite N-demethyldimethindene.
Experimental Part
Chemicals
Dimethindene maleate: Zyma SA (Nyon, Switzerland).- Fendiline
hydrochloride: Thiemann Arzneimittel (Waltrop, FRG).- N-Demethyldimethindene was synthesized as described4).- Acetonitrile and n-hexane
were LiChrosolvRreagents from Merck (Darmstadt, FRG).- Other chemicals were of analytical grade.
Apparatus
I
I
dimethindene
N-demethyldimethindene
A Varian 5000 Liquid Chromatographwith a variable wavelength detector 655A-22 (Merck-Hitachi) and a D-2000 Chromato-Integrator (MerckHitachi) were used.- The analytical column was a LiChrosphep 60 CN, 10
pm, 250 x 4 mm i d . (Merck), with a 30 x 4 m m i.d. guard-column of the
same sorbent. Mobile phase: 0.02M KH2FQ4-acetonitrile-water( W 3 2 8 ,
v/v/v).- Flow rate: 1.0 ml/min; column temp.: 25°C.- Detection wavelength: 254 nm.
R
CH3
H
Extraction procedure, calibration curve, assay precision, and recovery
from uring
This paper reports the application of this method to determine dimethindene and its metabolite in urine after topical
administration. The urinary data of eight volunteers are presented. The determination was performed on urine samples
of a study which was retrospectively chosen and, therefore,
had not an optimum design for this purpose. Just recently a
more sensitive HPLC-method for the determination of dim-
+)
dedicated to HJ. Roth on the occasion of this 65th birthday.
Arch. Pharm. (Weinheim)328,127-129 (1995)
For procedure and validation of the assay see4).Linearity was shown in a
range of 12-2416 ng of dimethindene and 24-312 ng of N-demethyldimethindene (amount injected into HPLC). The mean recovery is 101.3% for
dimethindene and 54.2% for N-demethyldimethindene.For sample preparation 11-28 ml were used.
In vivo study
Eight volunteers received 12 mg dimethindene maleate as a gel. The gel
was administered to the skin at 6 different times, 2 mg each time at 0 h,
4 h, 8 h, 12 h, 24 h, and 28 h. Since the study was a short term trial it was
0VCH VerlagsgesellschaftmbH, D-69451 Weinheim, 1995
0365-6233/95/0202-0127 $5.00 + ,2510
128
Radler and Blaschke
c
a
0
$
6
volunteer 2
volunteer 3
volunteer 4
volunteer 5
volunteer 6
volunteer 7
mean
0
10
20
30
time (h]
volunteer 1
volunteer 2
volunteer 3
volunteer 4
volunteer 5
volunteer 6
volunteer 8
mean
0
10
30
20
tlme Ihl
Fig. 1. Cumulative excretion curves of dimethindene and N-demethyldimethindene after dermal administration of 12 mg dimethindene to 8 healthy volunteers.
not possible to collect urine over a longer period. Urine was collected in 8
h intervals up to 32 h. Volume and pH were measured, and an aliquot was
stored at -20°C until analysis.
Results and Discussion
Dimethindene in human urine after topical administration
In the urine of almost all volunteers dimethindene as well
as N-demethyldimethindene could be detected. Fig. 1 shows
the cumulative excretion curves for dimethindene and
N-demethyldimethindene of eight volunteers after administration of 6 x 2 mg dimethindene to the skin. Table 1
shows the corresponding data of dimethindene and N-demethyldimethindene (mean values of the 8 volunteers). Unmetabolised dimethindene was observed only after the second
sample interval; in the urine of two volunteers dimethindene was not detectable. However, the metabolite N-demethyldimethindene was excreted by 7 of 8 volunteers. The
interindividual variations were quite large. An average of
0.023% dimethindene and 0.022% N-demethyldimethindene of the administered dose was excreted after 32 h. The
excretion of dimethindene and its metabolite has not yet
been completed 4 h after the last administration. Because
the study was designed as short term trial with a different
objective it was not possible to collect urine longer than for
32 h: the volunteers were no longer available.
Also, after oral administration only about 1% of the administered dose of dimethindene and 1.4% of N-demethyldimethindene were found in urine4).Taking this into account
it can be concluded that dimethindene is absorbed through
the skin to a certain extent. Due to the design of the study,
however, an estimate for the relative bioavailability after
dermal administration cannot be made.
The authors thank Dr. D.Rehn and Dr. H . Brunnauer (Zyma, Miinchen,
FXG) for providing the urine samples and the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and Zyma for financial
support.
References
1
2
3
4
5
E. Milsmann, P. Rohdewald,Dermatologica 1985,170,230-234.
P. Rohdewald,E. Milsmann, Pharm. Zeifg. 1986,131,2035-2038.
A. Dobozy, Z . Hautkr. 1973,48,787-790.
S . Radler, G. Blaschke, J . Chromatogr. 1991,567,229-239.
D. Chollet, P. Kiistner, M. Wermeille, J . Chromatogr. 1993, 629, 8993.
Arch. Pharm. (Weinheim) 328,127-129 (1995)
129
Transdermal Absorption of Dimethindene
Table 1: Dimethindene and N-demethyldimethindene in human urine after
dermal administration of 12 mg dimethindene
Dimethindene
Interval
conc.
cumulative
excreted
(h)
(ng/ml)
(P9)
(%
mean f SD
mean f SD
mean f SD
0-8
0
0
0
8-16
0.30 f 0.56
0.23 f 0.47
0.003 f 0.006
16-24
2.37 f 3.88
1.43 f 1.72
0.014 f 0.017
24 - 32
1.76 f 1.86
2.74 f 2.51
0.023 f 0.021
cumulative
excreted
(%
of dose) 1)
N-demethyldimethindene
.
Interval
conc
(h)
(ng/ml)
(P9)
mean f SD
mean f SD
mean f SD
0-8
0.69 f 1.41
0.50 f 0.97
0.008 f 0.016
8-16
0.42 f 0.80
0.84 f 1.43
0.012 f 0.018
16-24
1.03 f 1.56
1.52
f 1.64
0.015 f 0.016
24 - 32
1.55 f 1.15
2.64 f 2.25
0.022 f 0.019
~~
~
of d o s e ) l )
~
1) % of dose administered up t o t h i s time
[Ph266]
Arch. Pharm. (Weinheim) 328,127-129 (1995)
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