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Fish and antibiotics: Pharmacokinetics of sulphadimidine in carp (Cyprinus carpio)
Veterinary Immunology and Immunopathology, 12 (1986) 281--286 Elsevier Science Publishers B.V., Amsterdam -- Printed in The Netherlands
281
FISH AND ANTIBIOTICS: PHARMACOKINETICS OF SULPHADIMIDINE IN CARP (CYPRINUS CARPIO) J.L. i
GRONDEL1, J . F . M .
Department of
Agricultural
NOUWS2 and O.L.M.
Experimental
University,
Animal
P.O.
HAENEN1
Morphology
Box 338,
and C e l l
Biology,
6700 AH Wageningen,
The N e t h e r l a n d s 2 R.V.V.-District
6,
P.O.
Box 40010,
6504 AA N i j m e g e n ,
The N e t h e r l a n d s
ABSTRACT Grondel, J.L., Nouws, J . F . M . and Haenen, O . L . M . , 1986. F i s h and Antibiotics: Pharmacokinetics of sulphadimidine in carp (Cyprinus carpio). V e t . Immunol. I m m u n o p a t h o l . , 12: 2 8 1 - 2 8 6 . P h a r m a c o k i n e t i c s , metabolism and clearance of sulphadimidine (SDM) w e r e studied a f t e r a s i n g l e i n t r a p e r i t o n e a l i n j e c t i o n o f SDM in carp a t 20oc. SDM was a c e t y l a t e d and hydroxylated to a small e x t e n t . The m a i n m e t a b o l i t e was N4-acetyl d e r i v a t i v e amount i n g only 2% of the t o t a l drug d o s e excFeted; h y d r o x y l a t i o n was less important (0.41% of the dose). The e l i m i n a t i o n h a l f - l i f e f o r SDM in carp was 17.5h. The c l e a r a n c e v a l u e s f o r SDM and i t s m e t a b o l i t e s were e q u i v a l e n t . The importance of pharmacokinetic studies in d i f f e r e n t f i s h species is discussed. INTRODUCTION In l a r g e - s c a l e f i s h c u l t u r e , disease outbreaks can cause a subs t a n t i a l loss of animals. A n t i m i c r o b i a l drugs, o f t e n used as food a d d i t i v e s , are employed f o r p r o p h y l a c t i c and t h e r a p e u t i c purposes. In p r a c t i c e the dosage employed is mals.
This
may r e s u l t
in
often e x t r a p o l a t e d from mam-
unwanted side e f f e c t s .
p r e v i o u s l y presented papers
(Anderson et
al.,
As reported in
1984, Grondel
and
Boesten, 1982, Grondel et a l . ,
1985a, Grondel and Muiswinkel van,
1985b,
1984,
Muiswinkel
van et
al.,
b i o t i c s may i n t e r f e r e with i n d u c t i o n of residues in
bacterial
the
Rijkers e t
immune system.
r e s i s t a n c e and the
al.,
1981) a n t i -
F u r t h e r m o r e , the
occurrence of
drug
e d i b l e tissues can be a serious problem. A r a t i o n a l
and optimal plan f o r a n t i m i c r o b i a l therapy f o r f i s h is needed.
0165-2427/86/$03.50
© 1986 Elsevier Science Publishers B.V.
282
Sulphadimidine
(SDM) is
the most widely used sulphonamide for
prophylactic and therapeutic purposes administered to a wide range of
species.
SDM can be metabolized
by hydroxylation and by the
acetylation-deacetylation pathway (Vree et a l . , 1983, Vree et a l . , 1984, Vree and Hekster,
1985). The hydroxy metabolites are micro-
b i o l o g i c a l l y active and they may be potentiated by trimethoprim (Nouws et a l . , 1984). In t h i s paper we w i l l present pharmacokinetics
and metabolism of
SDM in
carp
(Cyprinus carpio)
following
i n t r a p e r i t o n e a l administration. MATERIALS AND METHODS Drugs Sodium sulphadimidineR (33.3%) was obtained from A.U.V. (Cuyk, The
Nethe r l ands) .
N4- a c e t y l sul p h a d i m i d i ne
(N4-SDM),
6-hydroxymethyl-sulphadimidine (SCH2OH) and 5-hydroxysulphadimidine
(SOH) w e r e synthesized and i s o l a t e d according
to Vree et
ai.(1984) and Vree and Hekster (1985). Experimental set up Carps, 6-8 months of age, were bred in our laboratory and kept in aquaria with aerated running tapwater at a temperature of 20oc. Animals were fed d a i l y with pelleted dry food (K30, Trouw & Co., Putten, The Netherlands) by means of a "Scharflinger" automatic feeder. For the experiment animals, weighing 179 ~ 12 gram, were kept i n d i v i d u a l l y in tanks with stagnant aerated tapwater (20°C). Water samples w e r e taken at 4 and 12 h i n t e r v a l s f o l l o w e d by replacement of tapwater (20°C). Sodium sulphadimidine (SDM) in solution was administered i n t r a p e r i t o n e a l l y to f i v e carp (lOOmg/fish). Heparinized blood samples (0.2 ml) were taken from the caudal vein at regular time i n t e r vals, centrifuged and frozen (-20oc)
pending HPLC analysis.
HPLC analysis Deglucuronidation, protein binding determination, sample preparation and HPLC analysis were performed as described by Nouws e__t a_~l. (1986a,b).
SDM, i t s
N4-SDM metabolite, and the two hydroxy-
metabolites were determined simultaneously in the samples. Pharmacokinetic
analysis
(Baggot,1977).
was
performed
by
standard
procedures
283 RESULTS Figure hours
1 shows the
after
concentration
the
plasma
parallel.
17.5 + 5.8 hours after
i0
the
dose a p p l i e d .
PLASMA CONC. 100-
their
SDM i n j e c t i o n .
SDM and
drug
carp
its
SDM was
recovery
con-
maximum
Beyond 20h
metabolites
half-life
Two
plasma
The m e t a b o l i t e
measured o v e r a p e r i o d The t o t a l
In
and r e a c h e d
The plasma e l i m i n a t i o n
(n=5)
SDM i n j e c t i o n .
48h was 64.4% o f
and 20h p o s t
one c a r p .
a maximum
ug/ml).
extent.
increased of
SDM f o r
mg/kg)
(124
to a small
concentrations
of
(75
observed
slowly
between
plasma
essentially
was
and a c e t y l a t e d in
concentrations p.i.
SDM i n j e c t i o n
(Cma x)
hydroxylated centrations
plasma d i s p o s i t i o n
a single
for
were
SDM was
o f 48 hours in
the w a t e r w i t h i n
The main m e t a b o l i t e
was N4-SDM
SULPHADIMIDINE I,R O\o'o0" O T12 13h ~ o
ug/ml
75 mg / kg
lO [
9h ,° ° ° ~ ' ° .....................~"~"--.......... o...
1
o~ S
"N 4
,,:
SCH20H
0 0 3 ~ 0
F i g . 1. bolites
10
2O
4O 6O hours afterinjection Plasma d i s p o s i t i o n o f s u l p h a d i m i d i n e (S) and i t s metaN 4 - a c e t y ] - ( N 4 ) , 5 - h y d r o x y - (S0H) and 6 - m e t h y l h y d r o x y -
sulphadimidine (SCH2OH) in plasma of a carp following i n t r a peritoneal administration of SDM (75 mg/kg).
284
and composed only 2% of the t o t a l
drug dose excreted. Hydroxyla-
t i o n was less important; 0.18% was excreted w i t h i n 48h as SOH and 0.23% as SCH2OH. The clearance values of SDM, N4-SDM and the h y d r o x y m e t a b o l i t e SCH20H were e q u i v a l e n t : 0.29, ml/kg/min
(n=5) r e s p e c t i v e l y . Plasma p r o t e i n
0.39 and 0.22
b i n d i n g data were
obtained from carp kept in tanks with stagnant water and in tanks continuously refreshed with running tapwater (20oc).
The percen-
tages plasma protein binding of SDM, N4-SDM and SCH20H w e r e 41.2 (n=6), 14.7 (n=2) and 33.8 (n=5), r e s p e c t i v e l y . DISCUSSION After
i.p.
injection
elimination ~ a l f - l i f e
is
SDM was absorbed q u i c k l y .
The plasma
a p p r o x i m a t e l y 17.5
SDM can be
metabolized by hydroxylation as well
hours.
as by a c e t y l a t i o n (Fig.
2).
Both the 5-hydroxysulphadimidine and the 6-hydroxymethylsulphadimidine metabolites were detected. However, in carp SDM was mainly converted i n t o N4-SDM, which i s in contrast to the observations in mammals.
In cows and calves SDM is e x t e n s i v e l y hydroxylated i n t o
hydroxy d e r i v a t i v e s and to a lesser extent acetylated i n t o N4-SDM (Nouws et a l . ,
1986a). H3
Sulphadlmldlne
NH
,o,
"CH 3
N4-acetyI sulphadtmtdtne
OH 5-0H-sulphadtmtdine
6-0Hmethyl-sul~adt~ ldtne \CH3
3
F i g . 2. M o l e c u l a r s t r u c t u r e s of s u l p h a d i m i d i n e and of i t s 5-hydroxy-4,6-dimethyl-pyrimidine, 6-hydroxymethyl-4-methylpyrimidine and N4-acetyl metabolite. Furthermore, the percentages of metabolites in carp plasma appeared to be n e i t h e r dependant on the dose nor dependant on replacement of tapwater (unpublished data). The N4-SDM and h y d r o x y m e t a b o l i t e s showed concentration-time curves running p a r a l l e l
to
SDM beyond 20h p . i . .
The clearance
values were equivalent and the e l i m i n a t i o n was predominantly by a
285
passive
diffusion
process.
ion-deacetylation The
It
pharmacokinetic laboratory
weight,
constant
carpio).
However, d i f f e r e n c e s
disease for
for
water
12°C)
and
carp
(kept
chloramphenicol trout
th e
sent.
some s p e c i e s It
on
ence i n
is
macokinetic needed
has to
age,
one
fish all
in
(unpublished
plasma
(kept
both
at for
rainbow
data).
data
are
scarce
dispositon
markedly.
and
times
However,
for
or
between mammalian s p e c i e s
distribution,
species
trout
data).
values
(Cyprinus
b e h a v i o u r can
half-life
rainbow
under
a certain
species
(unpublished half-life
kept
of
temperature,
between
pharmacokinetic
t h e body can d i f f e r
ces between f i s h It
20°C)
that
from
fish,
differences
observed
at
well-known
tissue
to
obvious
elimination
and carp were equal
For data
were
and
an a c e t y l a t -
n o t shown).
the p h a r m a c o k i n e t i c
respect
Recently,
oxytetracycline
obtained healthy
temperature in
observed that
(results
were
circumstances:
SDM w i t h
status.
exists
data
optimal
be e x p e c t e d
was a l s o
equilibrium
Similarly,
s p e c i e s may be e x p e c t e d w i t h
even
the
and drug
ab-
kinetic persist-
extreme d i f f e r e n -
respect
to the p h a r -
behaviour of drugs. to
be
emphasized
optimize
that
large-scale
pharmacological,
environmental
be e x t e n d e d o v e r
a wide range o f
management o f
fish
a multidisciplinary fish
culture.
and m i c r o b i o l o g i c a l species
to
approach
is
Immunological, research
support
the
has to
effective
culture.
REFERENCES Anderson, D.P., Muiswinkel van, W.B. and R o b e r s on, B . S . , 1984. Effects o f c h e m i c a l l y i n d u c e d immune m o d u l a t i o n on i n f e c t i o u s diseases of fish. I n : M. K e n d e , J . G a i n e r and M. C h i r i g o s ( e d s . ) , Chemical r e g u l a t i o n o f i m m u n i t y i n V e t e r i n a r y M e d i c i n e . A.R. L i s s e I n c . , New Y o r k , pp. 1 8 7 - 2 1 1 . Baggot, J.D., 1977. Principles o f drug d i s p o s i t i o n in domestic a n i m a l s . W.B. Saunders Co, P h i l a d e l p h i a / T o r o n t o , London. G r o n d e l , J . L . and B o e s t e n , H . J . A . M . , 1982. The i n f l u e n c e o f a n t i biotics on t h e immune system. I. Inhibition of the m i t o g e n i c leukocyte response in vitro by oxytetracycl ine. Dev.Comp.lmmunol., Suppl. ~ pp.---~-i-I--216. G r o n d e l , J . L . , Gloudemans, A.G.M. and M u i s w i n k e l van, W.B., 1985a. The i n f l u e n c e o f a n t i b i o t i c s on t he immune s y s t em. I I . Mo d u la tion of fish leukocyte responses in culture. V e t . Immunol. I m m u n o p a t h o l . , 9: 2 5 1 - 2 6 0 . G r o n d e l , J . L . and M u i s w i n k e l van, W.B., 1985b. I m m u n o l o g i c a l def e n c e mechanisms as a t a r g e t f o r a n t i b i o t i c s . In " C o m p a r a t i v e V e t e r i n a r y P h a r m a c o l o g y , T o x i c o l o g y and T h e r a p y , 3rd EAVPT cong r e s s , G h e n t " , A b s t r a c t s , p. 145.
286
M u i s w i n k e l van, W.B., A n d e r s o n , D.P., Lamers, C . H . J . , Egberts, E., Loon van, J . J . A . and I J s s e l , J . P . , 1984. Fish immunology and f i s h h e a l t h . Fish Immunology, M.J. Manning & M.F. T a t n e r , e d s . , Proceedings of the Plymouth Meeting 1983, Academic Press, London. Nouws, J . F . M . , Vree, T.B. and H e k s t e r , Y . A . , 1984. In v i t r o a n t i m i c r o b i a l a c t i v i t y of hydroxy and N 4 - a c e t y l - s u l f o ~ m ~ e t a b o lites. The V e t e r i n a r y Q u a r t e r l y , 7: 70-72. Nouws, J . F . M . , Vree, T . B . , Baakman, M., D r i e s s e n s , F . , H.J. Breukink and Mevius, D., 1986a. Age and dosage dependency in the plasma d i s p o s i t i o n and renal c l e a r a n c e of sulphamethazine and i t s N 4 - a c e t y l and hydroxy m e t a b o l i t e s in c a l v e s and cows. Am. J. Vet. Res., in p r e s s . Nouws, J . F . M . , Vree, T . B . , Baakman, M., D r i e s s e n s , F . , V e l l e n g a , L. and Mevius, D., 1986b. P h a r m a c o k i n e t i c s , r e n a l c l e a r a n c e , tissue distribution and r e s i d u e aspects of s u l p h a d i m i d i n e and i t s N 4 - a c e t y l m e t a b o l i t e in p i g s . The V e t e r i n a r y Q u a r t e r l y , 7, in p r e s s . Rijkers, G . T . , Oosterom van, R. and Muiswinkel van, W.B., 1981. The immune system of c y p r i n i d f i s h . Oxytetracycline and the r e g u l a t i o n of humoral immunity in carp. Vet. Immunol. Immunopat h o l . , 2: 281-290. Vree, T . B . , T i j h u i s , M., Baakman, M. and H e k s t e r , Y . A . , 1983. Anal y s i s of N 4 - t r i d e u t e r o a c e t y l s y l p h a m e r a z i n e and i t s m e t a b o l i t e s s u l p h a m e r a z i n e and N 4 - a c e t y l s u l p h a m e r a z i n e in man by means of h i g h - p e r f o r m a n c e l i q u i d chromatography and mass s p e c t r o m e t r y . Biomed. Mass. Spectrom., i 0 : 114-119. Vree, T . B . , T i j h u i s , M., Nouws, J.F.M. and H e k s t e r , Y . A . , 1984. Identification, isolation, c h r o m a t o g r a p h y , and p r e l i m i n a r y p h a r m a c o k i n e t i c s of 4 - h y d r o x y s u l f a m e r a z i n e in dogs. Pharmac. Weekbl., S c i . Ed., 6: 80-87. Vree, T.B. and Hekster, Y . A . , 1985. P h a r m a c o k i n e t i c s of s u l f o n a mides r e v i s i t e d . A n t i b i o t i c s and Chemotherapy, 34: 1-208.
281
FISH AND ANTIBIOTICS: PHARMACOKINETICS OF SULPHADIMIDINE IN CARP (CYPRINUS CARPIO) J.L. i
GRONDEL1, J . F . M .
Department of
Agricultural
NOUWS2 and O.L.M.
Experimental
University,
Animal
P.O.
HAENEN1
Morphology
Box 338,
and C e l l
Biology,
6700 AH Wageningen,
The N e t h e r l a n d s 2 R.V.V.-District
6,
P.O.
Box 40010,
6504 AA N i j m e g e n ,
The N e t h e r l a n d s
ABSTRACT Grondel, J.L., Nouws, J . F . M . and Haenen, O . L . M . , 1986. F i s h and Antibiotics: Pharmacokinetics of sulphadimidine in carp (Cyprinus carpio). V e t . Immunol. I m m u n o p a t h o l . , 12: 2 8 1 - 2 8 6 . P h a r m a c o k i n e t i c s , metabolism and clearance of sulphadimidine (SDM) w e r e studied a f t e r a s i n g l e i n t r a p e r i t o n e a l i n j e c t i o n o f SDM in carp a t 20oc. SDM was a c e t y l a t e d and hydroxylated to a small e x t e n t . The m a i n m e t a b o l i t e was N4-acetyl d e r i v a t i v e amount i n g only 2% of the t o t a l drug d o s e excFeted; h y d r o x y l a t i o n was less important (0.41% of the dose). The e l i m i n a t i o n h a l f - l i f e f o r SDM in carp was 17.5h. The c l e a r a n c e v a l u e s f o r SDM and i t s m e t a b o l i t e s were e q u i v a l e n t . The importance of pharmacokinetic studies in d i f f e r e n t f i s h species is discussed. INTRODUCTION In l a r g e - s c a l e f i s h c u l t u r e , disease outbreaks can cause a subs t a n t i a l loss of animals. A n t i m i c r o b i a l drugs, o f t e n used as food a d d i t i v e s , are employed f o r p r o p h y l a c t i c and t h e r a p e u t i c purposes. In p r a c t i c e the dosage employed is mals.
This
may r e s u l t
in
often e x t r a p o l a t e d from mam-
unwanted side e f f e c t s .
p r e v i o u s l y presented papers
(Anderson et
al.,
As reported in
1984, Grondel
and
Boesten, 1982, Grondel et a l . ,
1985a, Grondel and Muiswinkel van,
1985b,
1984,
Muiswinkel
van et
al.,
b i o t i c s may i n t e r f e r e with i n d u c t i o n of residues in
bacterial
the
Rijkers e t
immune system.
r e s i s t a n c e and the
al.,
1981) a n t i -
F u r t h e r m o r e , the
occurrence of
drug
e d i b l e tissues can be a serious problem. A r a t i o n a l
and optimal plan f o r a n t i m i c r o b i a l therapy f o r f i s h is needed.
0165-2427/86/$03.50
© 1986 Elsevier Science Publishers B.V.
282
Sulphadimidine
(SDM) is
the most widely used sulphonamide for
prophylactic and therapeutic purposes administered to a wide range of
species.
SDM can be metabolized
by hydroxylation and by the
acetylation-deacetylation pathway (Vree et a l . , 1983, Vree et a l . , 1984, Vree and Hekster,
1985). The hydroxy metabolites are micro-
b i o l o g i c a l l y active and they may be potentiated by trimethoprim (Nouws et a l . , 1984). In t h i s paper we w i l l present pharmacokinetics
and metabolism of
SDM in
carp
(Cyprinus carpio)
following
i n t r a p e r i t o n e a l administration. MATERIALS AND METHODS Drugs Sodium sulphadimidineR (33.3%) was obtained from A.U.V. (Cuyk, The
Nethe r l ands) .
N4- a c e t y l sul p h a d i m i d i ne
(N4-SDM),
6-hydroxymethyl-sulphadimidine (SCH2OH) and 5-hydroxysulphadimidine
(SOH) w e r e synthesized and i s o l a t e d according
to Vree et
ai.(1984) and Vree and Hekster (1985). Experimental set up Carps, 6-8 months of age, were bred in our laboratory and kept in aquaria with aerated running tapwater at a temperature of 20oc. Animals were fed d a i l y with pelleted dry food (K30, Trouw & Co., Putten, The Netherlands) by means of a "Scharflinger" automatic feeder. For the experiment animals, weighing 179 ~ 12 gram, were kept i n d i v i d u a l l y in tanks with stagnant aerated tapwater (20°C). Water samples w e r e taken at 4 and 12 h i n t e r v a l s f o l l o w e d by replacement of tapwater (20°C). Sodium sulphadimidine (SDM) in solution was administered i n t r a p e r i t o n e a l l y to f i v e carp (lOOmg/fish). Heparinized blood samples (0.2 ml) were taken from the caudal vein at regular time i n t e r vals, centrifuged and frozen (-20oc)
pending HPLC analysis.
HPLC analysis Deglucuronidation, protein binding determination, sample preparation and HPLC analysis were performed as described by Nouws e__t a_~l. (1986a,b).
SDM, i t s
N4-SDM metabolite, and the two hydroxy-
metabolites were determined simultaneously in the samples. Pharmacokinetic
analysis
(Baggot,1977).
was
performed
by
standard
procedures
283 RESULTS Figure hours
1 shows the
after
concentration
the
plasma
parallel.
17.5 + 5.8 hours after
i0
the
dose a p p l i e d .
PLASMA CONC. 100-
their
SDM i n j e c t i o n .
SDM and
drug
carp
its
SDM was
recovery
con-
maximum
Beyond 20h
metabolites
half-life
Two
plasma
The m e t a b o l i t e
measured o v e r a p e r i o d The t o t a l
In
and r e a c h e d
The plasma e l i m i n a t i o n
(n=5)
SDM i n j e c t i o n .
48h was 64.4% o f
and 20h p o s t
one c a r p .
a maximum
ug/ml).
extent.
increased of
SDM f o r
mg/kg)
(124
to a small
concentrations
of
(75
observed
slowly
between
plasma
essentially
was
and a c e t y l a t e d in
concentrations p.i.
SDM i n j e c t i o n
(Cma x)
hydroxylated centrations
plasma d i s p o s i t i o n
a single
for
were
SDM was
o f 48 hours in
the w a t e r w i t h i n
The main m e t a b o l i t e
was N4-SDM
SULPHADIMIDINE I,R O\o'o0" O T12 13h ~ o
ug/ml
75 mg / kg
lO [
9h ,° ° ° ~ ' ° .....................~"~"--.......... o...
1
o~ S
"N 4
,,:
SCH20H
0 0 3 ~ 0
F i g . 1. bolites
10
2O
4O 6O hours afterinjection Plasma d i s p o s i t i o n o f s u l p h a d i m i d i n e (S) and i t s metaN 4 - a c e t y ] - ( N 4 ) , 5 - h y d r o x y - (S0H) and 6 - m e t h y l h y d r o x y -
sulphadimidine (SCH2OH) in plasma of a carp following i n t r a peritoneal administration of SDM (75 mg/kg).
284
and composed only 2% of the t o t a l
drug dose excreted. Hydroxyla-
t i o n was less important; 0.18% was excreted w i t h i n 48h as SOH and 0.23% as SCH2OH. The clearance values of SDM, N4-SDM and the h y d r o x y m e t a b o l i t e SCH20H were e q u i v a l e n t : 0.29, ml/kg/min
(n=5) r e s p e c t i v e l y . Plasma p r o t e i n
0.39 and 0.22
b i n d i n g data were
obtained from carp kept in tanks with stagnant water and in tanks continuously refreshed with running tapwater (20oc).
The percen-
tages plasma protein binding of SDM, N4-SDM and SCH20H w e r e 41.2 (n=6), 14.7 (n=2) and 33.8 (n=5), r e s p e c t i v e l y . DISCUSSION After
i.p.
injection
elimination ~ a l f - l i f e
is
SDM was absorbed q u i c k l y .
The plasma
a p p r o x i m a t e l y 17.5
SDM can be
metabolized by hydroxylation as well
hours.
as by a c e t y l a t i o n (Fig.
2).
Both the 5-hydroxysulphadimidine and the 6-hydroxymethylsulphadimidine metabolites were detected. However, in carp SDM was mainly converted i n t o N4-SDM, which i s in contrast to the observations in mammals.
In cows and calves SDM is e x t e n s i v e l y hydroxylated i n t o
hydroxy d e r i v a t i v e s and to a lesser extent acetylated i n t o N4-SDM (Nouws et a l . ,
1986a). H3
Sulphadlmldlne
NH
,o,
"CH 3
N4-acetyI sulphadtmtdtne
OH 5-0H-sulphadtmtdine
6-0Hmethyl-sul~adt~ ldtne \CH3
3
F i g . 2. M o l e c u l a r s t r u c t u r e s of s u l p h a d i m i d i n e and of i t s 5-hydroxy-4,6-dimethyl-pyrimidine, 6-hydroxymethyl-4-methylpyrimidine and N4-acetyl metabolite. Furthermore, the percentages of metabolites in carp plasma appeared to be n e i t h e r dependant on the dose nor dependant on replacement of tapwater (unpublished data). The N4-SDM and h y d r o x y m e t a b o l i t e s showed concentration-time curves running p a r a l l e l
to
SDM beyond 20h p . i . .
The clearance
values were equivalent and the e l i m i n a t i o n was predominantly by a
285
passive
diffusion
process.
ion-deacetylation The
It
pharmacokinetic laboratory
weight,
constant
carpio).
However, d i f f e r e n c e s
disease for
for
water
12°C)
and
carp
(kept
chloramphenicol trout
th e
sent.
some s p e c i e s It
on
ence i n
is
macokinetic needed
has to
age,
one
fish all
in
(unpublished
plasma
(kept
both
at for
rainbow
data).
data
are
scarce
dispositon
markedly.
and
times
However,
for
or
between mammalian s p e c i e s
distribution,
species
trout
data).
values
(Cyprinus
b e h a v i o u r can
half-life
rainbow
under
a certain
species
(unpublished half-life
kept
of
temperature,
between
pharmacokinetic
t h e body can d i f f e r
ces between f i s h It
20°C)
that
from
fish,
differences
observed
at
well-known
tissue
to
obvious
elimination
and carp were equal
For data
were
and
an a c e t y l a t -
n o t shown).
the p h a r m a c o k i n e t i c
respect
Recently,
oxytetracycline
obtained healthy
temperature in
observed that
(results
were
circumstances:
SDM w i t h
status.
exists
data
optimal
be e x p e c t e d
was a l s o
equilibrium
Similarly,
s p e c i e s may be e x p e c t e d w i t h
even
the
and drug
ab-
kinetic persist-
extreme d i f f e r e n -
respect
to the p h a r -
behaviour of drugs. to
be
emphasized
optimize
that
large-scale
pharmacological,
environmental
be e x t e n d e d o v e r
a wide range o f
management o f
fish
a multidisciplinary fish
culture.
and m i c r o b i o l o g i c a l species
to
approach
is
Immunological, research
support
the
has to
effective
culture.
REFERENCES Anderson, D.P., Muiswinkel van, W.B. and R o b e r s on, B . S . , 1984. Effects o f c h e m i c a l l y i n d u c e d immune m o d u l a t i o n on i n f e c t i o u s diseases of fish. I n : M. K e n d e , J . G a i n e r and M. C h i r i g o s ( e d s . ) , Chemical r e g u l a t i o n o f i m m u n i t y i n V e t e r i n a r y M e d i c i n e . A.R. L i s s e I n c . , New Y o r k , pp. 1 8 7 - 2 1 1 . Baggot, J.D., 1977. Principles o f drug d i s p o s i t i o n in domestic a n i m a l s . W.B. Saunders Co, P h i l a d e l p h i a / T o r o n t o , London. G r o n d e l , J . L . and B o e s t e n , H . J . A . M . , 1982. The i n f l u e n c e o f a n t i biotics on t h e immune system. I. Inhibition of the m i t o g e n i c leukocyte response in vitro by oxytetracycl ine. Dev.Comp.lmmunol., Suppl. ~ pp.---~-i-I--216. G r o n d e l , J . L . , Gloudemans, A.G.M. and M u i s w i n k e l van, W.B., 1985a. The i n f l u e n c e o f a n t i b i o t i c s on t he immune s y s t em. I I . Mo d u la tion of fish leukocyte responses in culture. V e t . Immunol. I m m u n o p a t h o l . , 9: 2 5 1 - 2 6 0 . G r o n d e l , J . L . and M u i s w i n k e l van, W.B., 1985b. I m m u n o l o g i c a l def e n c e mechanisms as a t a r g e t f o r a n t i b i o t i c s . In " C o m p a r a t i v e V e t e r i n a r y P h a r m a c o l o g y , T o x i c o l o g y and T h e r a p y , 3rd EAVPT cong r e s s , G h e n t " , A b s t r a c t s , p. 145.
286
M u i s w i n k e l van, W.B., A n d e r s o n , D.P., Lamers, C . H . J . , Egberts, E., Loon van, J . J . A . and I J s s e l , J . P . , 1984. Fish immunology and f i s h h e a l t h . Fish Immunology, M.J. Manning & M.F. T a t n e r , e d s . , Proceedings of the Plymouth Meeting 1983, Academic Press, London. Nouws, J . F . M . , Vree, T.B. and H e k s t e r , Y . A . , 1984. In v i t r o a n t i m i c r o b i a l a c t i v i t y of hydroxy and N 4 - a c e t y l - s u l f o ~ m ~ e t a b o lites. The V e t e r i n a r y Q u a r t e r l y , 7: 70-72. Nouws, J . F . M . , Vree, T . B . , Baakman, M., D r i e s s e n s , F . , H.J. Breukink and Mevius, D., 1986a. Age and dosage dependency in the plasma d i s p o s i t i o n and renal c l e a r a n c e of sulphamethazine and i t s N 4 - a c e t y l and hydroxy m e t a b o l i t e s in c a l v e s and cows. Am. J. Vet. Res., in p r e s s . Nouws, J . F . M . , Vree, T . B . , Baakman, M., D r i e s s e n s , F . , V e l l e n g a , L. and Mevius, D., 1986b. P h a r m a c o k i n e t i c s , r e n a l c l e a r a n c e , tissue distribution and r e s i d u e aspects of s u l p h a d i m i d i n e and i t s N 4 - a c e t y l m e t a b o l i t e in p i g s . The V e t e r i n a r y Q u a r t e r l y , 7, in p r e s s . Rijkers, G . T . , Oosterom van, R. and Muiswinkel van, W.B., 1981. The immune system of c y p r i n i d f i s h . Oxytetracycline and the r e g u l a t i o n of humoral immunity in carp. Vet. Immunol. Immunopat h o l . , 2: 281-290. Vree, T . B . , T i j h u i s , M., Baakman, M. and H e k s t e r , Y . A . , 1983. Anal y s i s of N 4 - t r i d e u t e r o a c e t y l s y l p h a m e r a z i n e and i t s m e t a b o l i t e s s u l p h a m e r a z i n e and N 4 - a c e t y l s u l p h a m e r a z i n e in man by means of h i g h - p e r f o r m a n c e l i q u i d chromatography and mass s p e c t r o m e t r y . Biomed. Mass. Spectrom., i 0 : 114-119. Vree, T . B . , T i j h u i s , M., Nouws, J.F.M. and H e k s t e r , Y . A . , 1984. Identification, isolation, c h r o m a t o g r a p h y , and p r e l i m i n a r y p h a r m a c o k i n e t i c s of 4 - h y d r o x y s u l f a m e r a z i n e in dogs. Pharmac. Weekbl., S c i . Ed., 6: 80-87. Vree, T.B. and Hekster, Y . A . , 1985. P h a r m a c o k i n e t i c s of s u l f o n a mides r e v i s i t e d . A n t i b i o t i c s and Chemotherapy, 34: 1-208.