Pharmacokinetics and Residues of Sulfadimidine and Its N4-Acetyl

15

Pharmacokinetics and Residues of Sulfadimidine 4

and Its N -Acetyl and Hydroxy Metabolites in Food-Producing Animals

1

2

3

4

J. F. M.Nouws ,T. B.Vree ,R.Aerts ,and J. Grondel

Downloaded by CORNELL UNIV on August 22, 2016 | http://pubs.acs.org Publication Date: September 18, 1986 | doi: 10.1021/bk-1986-0320.ch015

1

R.V.V.-District 6, P.O.Box 40010, Nijmegen, the Netherlands Department of Clinical Pharmacy, Sint Radboud Hospital, Nijmegen, the Netherlands RIKILT, Wageningen, the Netherlands ZODIAC, University of Wageningen, the Netherlands

2

3

4

Employing s p e c i f i c HPLC methods, the pharmacokinetics of sulfadimidine (SDM) and its metabolites N -acetyl (N -SDM), 6-hydroxymethyl (SCH OH), 5-hydroxy (SOH), and g l u c u r o n i d e (SOH-gluc.) were s t u d i e d i n v a r i o u s s p e c i e s . In general the SDM e l i m i n a t i o n half-lives depended on the metabolic rate and extent of metabolism as well as the renal excretion rate of the metab o l i t e s . N -SDM, SCH OH and SOH metabolites exhibited higher renal clearance values than SDM. Hydroxylation of SDM dominates in horses, c a l v e s , cows, and l a y i n g hens. The main metabolite i n horses was SOH; i n ruminants, SCH OH. In c a l v e s and cows at high dose l e v e l s (100 SDM mg/kg), a biphasic elimination SDM plasma concentration-time curve was observed with a steady state plasma SCH OH c o n c e n t r a t i o n r e s u l t i n g from the c a p a c i t y l i m i t e d hydroxylation of SDM into the l a t t e r . The drug concentrations i n the milk reflected those i n plasma. In calves and pigs, the SDM concentration i n plasma exceeded that in muscle, kidney or liver t i s s u e . The N -SDM t i s s u e c o n c e n t r a t i o n was lower than that of SDM; in the c a l v e s kidney, the SCH OH c o n c e n t r a t i o n exceeded that of SDM. In pigs, the acetylation pathway was predominant; no hydroxy metabolites could be detected i n plasma and edible tissues. Eggs layed within 7 days after SDM therapy (100 mg SDM/kg/day) has been t e r m i n a t e d show d e t e c t a b l e q u a n t i t i e s of the parent drug and its metabolites. 4

4

2

4

2

2

2

4

2

There are three main v a r i a b l e s governing the p h a r m a c o k i n e t i c s of sulfonamides i n animals,namely : 1) the molecular structure of the sulfonamide, 2) the mechanism and route of metabolism and 3) the r e n a l e x c r e t i o n . By s e l e c t i n g one sulfonamide, e.g. s u l f a d i m i d i n e (SDM), for a comparative study, one i s able to study species d i f f e 0097-6156/86/0320-0168S06.00/ 0 © 1986 American Chemical Society

Moats; Agricultural Uses of Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1986.


15.

Pharmacokinetics and Residues of Sulfadimidine

NOUWSETAL.

169

rences i n metabolism , t i s s u e d i s p o s i t i o n and r e n a l c l e a r a n c e s . Numerous r e p o r t s d i s c u s s i n g s p e c i e s d i f f e r e n c e s i n e l i m i n a t i o n h a l f - l i v e s for SDM as well as other sulfonamides, have been reviewed s u l f a d i m i d i n e i n e.g. horses, p i g s , ruminants, f o w l s , f i s h are obtained by the Bratton & Marshall method, which cannot d i s t i n g u i s h SDM from i t s hydroxy metabolites. Recently the hydroxy metabolites of various sulfonamides could be isolated and p u r i f i e d , so that s p e c i f i c HPLC techniques could be developed (22,23). As shown i n Figure 1, sulfadimidine can be metabolized by hydroxylation at the 5 and 6 p o s i t i o n of the pyrimidine r i n g and by the a c e t y l a t i o n - d e a c e t y l a t i o n pathway (21). A f t e r hydroxylation, the metabolites may become g l u c u r o n i d a t e d and a l s o acetylated (Figure 2). The hydroxy metabolites are m i c r o b i o l o g i c a l l y active and they can be potentiated by trimethoprim (13). Because of i t s widespread therapeutic use and because the question of residues i n food producing animals, SDM was selected for a study between species to compare i t s metabolism , the pharmacokinetics of the parent drug as w e l l as i t s metabolites. Residue depletion studies were performed i n edible tissues of calves, pigs and in the eggs of laying-hens.

MATERIAL AND METHODS Drugs Sodium sulfadimidine (33.3%) was obtained from A.U.V. (Cuyk,The Netherlands). N^-acetylsulfadimidine (N^-SDM), 6 - h y d r o x y m e t h y l - s u l f a d i m i d i n e (SCH OH) and 5-hydroxysulfadimidine (SOH) were synthesized and isolated according Vree et a l . (22,23). 2

Experiments Animals were obtained from Mr. van Raay i n G a s s e l , the C e n t r a l Animal Laboratory at the University of Nijmegen, Large Animal C l i nics at the University of Utrecht, and from Zodiac at the A g r i c u l t u r a l University of Wageningen, the Netherlands. SDM was a d m i n i s t e r e d e i t h e r i n t r a v e n o u s l y , i n t r a m u s c u l a r l y , o r a l l y , or i n t r a p e r i t o n e a l l y to horses, calves, cows, pigs, l a y i n g hens and carp. Heparinized blood samples were taken at regular time i n t e r v a l s , centrifuged and plasma was deep frozen at -20 C pending HPLC a n a l y s i s . Urine was c o l l e c t e d by e i t h e r spontaneous v o i d i n g , catheterisation, or with special c o l l e c t i o n urine and feces f a c i l i t i e s for the horses, ruminants, and pigs. When the pigs and calves were s l a u g h t e r e d , specimens of kidney, l i v e r , muscle, plasma, and u r i n e were sampled and prepared as d e s c r i b e d (16). The eggs of laying hens were collected during SDM administration and for the 14 days post administration. For the carp, water samples were taken at 4 to 12 h i n t e r v a l s , after which the water was changed. HPLC Analysis D e g l u c u r o n i d a t i o n , sample p r e p a r a t i o n and HPLC analysis were performed as described elsewhere (14,15,16). SDM, i t s N^-SDM, and two hydroxymetabolites were determined s i multaneously i n the several test specimen.


AGRICULTURAL USES OF ANTIBIOTICS


170

F i g u r e 1. M o l e c u l a r s t r u c t u r e s of s u l f a d i m i d i n e (SDM), i t s 5hydroxy-4,6-dimethyl-pyrimidine (SOH), i t s 6-hydroxymethyl-4m e t h y l - p y r i m i d i n e (SCH 0H) and i t s N / - a c e t y l m e t a b o l i t e ( N SDM)• * * 9

A

Z

Glucuronldation

SCOOH^

1?

N^-SCOOH ?

2? OXIDATION?

Other pathways -desamination -glycoside ? -ornithine ? -glycine ? -sulfation ?

-SCHoOH.

"\

1

NrSCH20H—i

2?

6-methyl hydroxylation

SDM:

Nil -SDM

5-hydroxylation

-Hi|-S0H

SOH 1 = Acetylation 2 = Deacetylation

2?

GlucuronidationFigure 2. Metabolic pathways of sulfadimidine.


15.

NOUWSETAL.


171

RESULTS


Table I summarizes the percentages of sulfadimidine and i t s metabol i t e s i n the plasma of the d i f f e r e n t s p e c i e s ; Table I I shows the tissue to plasma drug concentration ratios for SDM and i t s metabol i t e s , while Table III presents the urinary recovery data (for poultry urinary plus faecal recovery). The metabolic pathways observed i n various species are summarized i n a scheme (Figure 2). Selected data obtained are i l l u s t r a t e d i n Figures 3 - 9 . Horses In the horse, hydroxylation i s more important than acetylation as a metabolic pathway, with hydroxylation at the 5 p o s i t i o n being dominant over h y d r o x y l a t i o n of the 6-methyl group. Low percentages of m e t a b o l i t e s are present i n plasma, f o r N^-SDM, 0.6 to 0.9 %; f o r SCH 0H, 0.38 to 0.71 %; and f o r SOH, 0.38 to 6.7 %. The plasma concentration-time curves of the metabolites run p a r a l l e l to that of SDM. The elimination h a l f - l i f e of sulfadimidine varies between 5 and 14 h. The main metabolite i n urine, accounting for 50 % of the drugs present (Table III), i s the SOH and i t s glucuronide. 2

Cows and calves SDM i s 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 into N^-SDM. Hydroxylation of the 6-methyl group to form 6-hydroxymethylsulfadimidine dominates (1.5 times) h y d r o x y l a t i o n at the 5 p o s i t i o n (Table I I I ) . At h i g h dosage levels! (100 -200 mg/kg), a biphasic e l i m i n a t i o n SDM plasma concentrationtime curve was observed with a steady state plasma concentration of SCH 0H (6-15 ^/lg/ml) during the period i n which the SDM plasma concentration exceeded 20 jug/ml. A c a p a c i t y l i m i t e d h y d r o x y l a t i o n of SDM into SCH^OH was noticed i n ruminant calves and cows at a dosage l e v e l of 100-200 mg/kg (15). An unknown m e t a b o l i t e (X) and i t s glucuronide was detected either i n the plasma (Figure 3) or urine of cows, goats, and horses (Table I and III). The unknown metabolite (X) may be the f u r t h e r o x i d a t i o n product of the 6-hydroxymethyl metabolite. In which case i t was tentatively assumed to be 6-carboxysulfadimidine and i t s glucuronide. (In c a l c u l a t i n g the concentration of the unknown metabolite, which eluted from the HPLC column just before the 5-hydroxy metabolite (SOH), the molar extinction of SOH was used). This unknown metabolite did not penetrate the udder (Figure 4) presumably because of i t s polar nature. The N^-SDM plasma concentrations run p a r a l l e l to SDM beyond 4 h after i n j e c t i o n at a l l dosages i n a l l animals. In m i l k , the c o n c e n t r a t i o n of SDM and i t s m e t a b o l i t e s was a r e f l e c t i o n of those i n plasma (14; Figure 4). The d i s p o s i t i o n of SDM i n plasma , edible tissues, b i l e and urine of calves are i l l u s t r a t e d i n Figure 5. As shown, the SDM concentration i n plasma was higher than that i n the edible tissues. The l a t t e r i s also confirmed by the tissue to plasma concentration ratios of SDM and i t s metabolites which were lower than 1, except for the metabolite ratios i n kidney tissue (Table II). The SCH 0H concentration i n the kidney exceeded those of SDM (Figure 6). The N^-SDM m e t a b o l i t e c o n c e n t r a t i o n s i n muscle, kidney and l i v e r were always below those of SDM (Table II; 2

2



20-200 95.0

87.8 96.8

100

20

100

Goat

Horse

Pigs

Poultry

Flsh(carp) 560

+

0.4

2.8

t

1.2

4.5

7.5

0.05

—

—

10.0

3.8

0.5

0.7

a

5.4

7.2

m

3.9 1.0

22.4 9.7

2.1 2.3 1.5

1.4 0.7

30.9 8.6

5.7 11.0

— —

— —

32.7 67.3

2

X SCH OH X SOH

4

X N -SDM

—

—

—

—

8.5

3.4 2.2

— —

— —

XX ^ ^ j

v

t a b o l i t e 8

(a) S = slow acetylator phenotype; F ™ fast acetylator phenotype. 1) Percentage of ADC vs total ADC (= ADC «e )•

90.0

77.6

70.5 85.4

10 100

Cow

62.6 79.7

57.6 23.5

12 12

10 100

a

X SDM

Dose

Calf

Man ( S ) (F)

SPECIES

16

17

15 15

15 15

Reference

Table I MEAN PERCENTAGES OF SULFADIMIDINE AND ITS METABOLITES IN PLASMA OF DIFFERENT SPECIES.


15.

NOUWS ET AL.

173


Table II CONCENTRATION RATIO'S OF SULFADIMIDINE AND ITS METABOLITES BETWEEN TISSUE SPECIMEN AND PLASMA.


Drug concentration in specimen vs. plasma Calves

SIM

SCH 0H 2

SOH

N-SDM 4

3

Mean and standard deviation .

Kidney vs plasma

0.34+0.18 1.89+1.18 4.76+1.14 2.50+0.54 (n-11) (n-4) (n-3) (n-12)

Muscle ) vs plasma homogenate)

0.38+0.18 0.36+0.10 0.18+0.02 0.20+0.04 (n-4) (n-4) (n-10) (n-3)

Muscle drip vs plasma

0.39+0.20 0.32+0.02 0.23+0.13 0.38+0.06 (n-4) (n-4) (n-10) (n-5)

Liver vs plasma

0.24+0.18 0.27+0.13 0.31+0.20 0.43+0.18 (n-3) (n-7) (n-3) (n-3)

Pigs Kidney vs plasma

0.29+0.06 (n-10)

—

—

1.26+0.67 (n-9)

Muscle homogenate vs plasma

0.19+0.08 (n-10)

—

—

0.38+0.23 (n-10)

Muscle drip vs plasma

0.42+0.15 (n-11)

—

—

0.45+0.23 (n-10)

Liver vs plasma

0.15+0.12 (n-8)

—

—

0.33+0.30 (n-4)

a - Number of samples i n parentheses. — = absent



100

200

560

Goat

Horse

Fish (carp) Man ( S ) (F)

Poultry

20

Pigs

— a) b) c) d)

100

12 12

10 100

Cow

d

10 100

Calf

2 e

e

84 88

a

a

0-60 0-60

0-48

0-27

42

88 87

64.4

25

98

13.9

12.9 3.6

62.2

12.1

62.5 74.1

1.8

1.4 10.1 (40.5 )(5.6) C

41.0

13.4 4.5

7.2 9

9.7 26

15.1

13 34

7 22

4

10.2

6.3 7.0

0.23

0.25 (1.0)

28.2

18.7

50.5 26

50 26

b

2

—

—

4.7

5.8

3.5 0.75

0.18

12.7 (51)

30.9

— — —

—

—

—

2.8 1.56

—

0.4 (1.4)

18.2

4.8 2.3

— 0.2

18.0 8

1.4

— —

— —

14 6

= not detected Diphasic elimination-time curve (both elimination half-lives given). present as an acetylated derivative. relative percentage of the total recovered drug i n 27 h i n parenthesis S = slow acetylator phenotype; F = fast acetylator phenotype

101-3.5 0-60

7.7 1.6+5

17.5

9.5

2.7-3.8 0-20

0-140 77.8

0-72 0-120

m

9-14

a

i

86 72

T

3.5 0-72 12+6.5 0-72

a

3.5 15+5

1

PLASMA ELIMINATION HALF-LIFE, AND URINARY RECOVERY OF SULFADIMIDINE AND ITS METABOLITES EXPRESSED AS PERCENTAGES OF THE DOSE ADMINISTERED (mean values) IN DIFFERENT SPECIES. SPECIES Dose T y l URINARY RECOVERY EXPRESSED AS PERCENTAGE OF THE DOSE period mg/kg hours in Total ZSDM ZN -SDM %SCH OH ZSOH ZX ZX,glue hours recovery (+gluc)

Table III


00

H o

o

55

> Z H

O

r c m

>

c

^

o c

15.

NOUWS ET AL.


175


Concentration, /ug/ml plasma

F i g u r e 3. Plasma c o n c e n t r a t i o n - t i m e curves of s u l f a d i m i d i n e (SDM), and i t s 6-methylhydroxy (CH-OH), 5-hydroxy (SOH) and i t s g l u c u r o n i d e ( S O H i ) > N ^ - a c e t y l CN^) and unknown (X) metabol i t e s i n a cow after an intravenous dose of 200 mg/kg s u l f a d i m i dine. g

uc

Concentration, AJg/ml m i l k

Figure 4. Disposition of sulfadimidine (SDM), i t s 6-methylhydroxy (CH^OH), 5-hydroxy (SOH) and N ~ a c e t y l ( N ) m e t a b o l i t e s i n milk or a dairy cow following intravenous administration of 200 mg SDM/kg. 4

4


176



Concentration, /ug/ml o r g t i s s u e

0

1

2

3

D a y s

a f t e r

administration

F i g u r e 5. D i s p o s i t i o n of s u l f a d i m i d i n e i n u r i n e , b i l e , plasma and tissues of calves following intravenous administration of 65 mg/kg intravenously.



NOUWS ET AL.


111

F i g u r e 6. D i s p o s i t i o n of sulfadimidine(SDM), 6-methylhydroxy (CHoOH), and N^-acetylsulfadimidine ( N ) i n the kidney of calves following intravenous administration of 65 mg SDM/kg. 4



178


T-,6.4 H

0.1SULFADIMIDINE ORALLY Multiple doslngdOO mg/kg) (1)

Z

0.01.

1

I

L oti

s

50 100(4) 15

Pharmacokinetics and Residues of Sulfadimidine and Its N4-Acetyl

Recommend Documents