BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 7 , 239-252 (1986)

PHARMACOKINETICS, METABOLISM AND RENAL EXCRETION OF SULFATROXAZOLE

METABOLITES IN MAN AND ITS 5-HYDROXY- AND N4-ACETYL-

T. B . VREE*?, Y . A. HEKSTER*, M . w. TIJHUIS*, E. F. s. TERMOND*

A N D J . F. M . NOUWSS

Departments of Clinical Pharmacy* and Anesthesiology f , Sint Radhoud Hospital, University of Nijmegen. Nijmegen. The Netherlands arid SMeai Inspection Service. Woljskirilseweg 27'9.

Nijmegen, The Netherlands

ABSTRACT

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N,-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation. which results in an increase of the of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.

KEY WORDS Sulfatroxazole N,-acetylsulfatroxazole 5-Hydroxysulfatroxazole Acetylation Deacetylation Hydroxylation Renal clearance Inhibition of renal clearance Protein binding Probenecid Active tubular secretion

INTRODUCTION

Sulfatroxazole (3-sulfanilamido-4,5-dimethyloxazoyl) is a sulfonamide drug under investigation. The structure is closely related to that of sulfamethox- azole; there is a methyl group substituted at the 4 position. It can be anticipated that the pharmacokinetics of sulfatroxazole resembles that of sulfamethoxazole, i.e. that the main metabolic pathway of elimination will proceed by acetylation.* On the other hand, sulfatroxazole is a structure

0142-2782/86/030239-14~07 .OO @ 1986 by John Wiley & Sons, Ltd.

Received 10 October 1984 Revised 3 June 1985

240 T. B . VREE ET A L .

analogue of other dimethyloxazoyl sulfonamides such as sulfafurazole (sulfisoxazole), and sulfamoxole and the drug may show kinetic behaviour comparable to these analogues.

Sulfonamides are metabolized by the acetylation-deacetylation p a t h ~ a y s l ~ ~ " * ' ~ and by hydroxylation of the N , - s ~ b s t i t u e n t . ~ ' ~ ~ ~ ~ ~ ~ ~ * ' ~ ~ ~ ~ Th e acetylation and hydroxylation metabolic pathways are complementary to each other in the elimination of the sulfonamides. If 90 per cent of the parent drug with its N4-acetylsulfonamide metabolite is recovered in the urine after a period of 7 half-lives, the missing 10 per cent of the mass balance may be explained by incomplete absorption from the gastrointestinal tract or by hydroxylation. If the missing part of the mass balance increases to 75-90 per cent, explanation by an incomplete absorption seems less likely for soluble sulfonamides. and unidentified hydroxy metabolites must be assumed to be the reason for this incomplete recovery.

Pilot studies with sulfatroxazole in man showed that sulfatroxazole is only acetylated for 15 per cent, another 10 per cent is excreted unchanged in the urine, while 75 per cent of the administered dose is missing.'* The pharmacokinetic analysis of sulfatroxazole is complete when a possible hydroxy metabolite is also measured, then the mass balance of the excreted compounds is 100 per cent. Synthesis of the hydroxy metabolite(s) of sulfatroxazole occurred in beagle dogs, followed by isolation from the dog's urine.I4 It turned out that both dog and man hydroxylated sulfatroxazole as sulfarnethoxazole at the 5-methyl

In this paper the following pharmacokinetic parameters of sulfatroxazole are described: rates of acetylation-deacetylation, hydroxylation, protein binding, renal clearance, and mechanism of renal excretion of the parent drug and its 5-hydroxy- and N4-acetyl metabolites.

MATERIALS AND METHODS

Drugs Sulfatroxazole and N4-acetylsulfatroxazole were obtained from Lovens

Kerniske Fabrik (Copenhagen, Denmark). 5-Hydroxysulfatroxazole was isolated from dog urine in a way analogous to that described earlier for 4-hydroxysulfamerazine. l 3 NMR and HPLC data of 5-hydroxysulfatroxazole are fully described elsewhere.I4 The molecular structures of the compounds are given in Figure 1. Probenecid (Benemid) was obtained from MSD (Haarlem, The Netherlands).

Subjects In total 8 healthy Caucasian volunteers (6 males, 2 females, 4 'fast' and 4

'slow' acetylators) with ages ranging from 20 to 41 years, participated in the study. Three volunteers participated in a pilot study, in which preliminary

SULFATROXAZOLE PHARMACOKINETICS 241

5-OH-sulfatroxazole L

Cl-b-!+ti-@fN-ll7~~~~ 0

N’o CH, M-acetvl su I fat roxazole

Figure 1. Structural formulas of sulfatroxazole and its metabolites 5-hydroxy- and N4- ace t ylsulfatroxazole

kinetics of parent drug and N4-acetyl metabolite were obtained. Six volunteers (3 fast and 3 slow acetylators) participated in the main study, in which the hydroxy metabolite was included. Sulfatroxazole was administered orally in gelatine capsules, in doses ranging from 400 to 850mg. A dose of 2.5g of probenecid was taken as co-medication by 1 volunteer during the elimination phase of sulfatroxazole.

Drug analysis Sulfatroxazole and its N4-acetyl- and 5-hydroxy metabolite were measured

by HPLC analysis as previously described. I 4 . l 5 The mobile phase is a mixture of 70.6 per cent sodium acetate (0.1 M), 12.4 per cent acetic acid (0.1 M), and 17 per cent acetonitrile. A 15cm X 4.6mm ID column is packed with Lichrosorb RP-8, particle size 5pm. Detection is achieved at 269nm. The capacity factors for sulfatroxazole and its 5-hydroxy- and N4-acetyl metabolite are, respectively, 5.9, 1.0, and 4-6. Probenecid was measured on a 15 cm X 4.6 mm ID column packed with Lichrosorb RP8, particle size 5 pm. The mobile phase consisted of 55 per cent sodium acetate (0.02 M) and 45 per cent methanol at a flow rate of 2-0 ml min-’. The capacity factor of probenecid is 4.0.

Sampling procedures Blood. 2ml blood samples were collected at regular time intervals by

means of fingertip puncture with Monolet@ lancets (Monoject, St. Louis, USA). After centrifugation plasma samples were stored at -20” until analysis.

242 T. 0. VREE ET AL.

Urine. Urine was collected on spontaneous voiding. The total time of sample collection varied between 100 and 150 h (7 half-lives). Urinary pH was measured immediately after collection. Measurements were made with a Radiometer (Copenhagen PMH61) instrument. Urine samples of 5 ml were stored at -20" until analysis.

Protein binding Protein binding of sulfatroxazole and its metabolites, 5-hydroxy- and

N4-acetylsulfatroxazole, was measured by means of EMITe Free level filters (SYVA, Palo Alto, USA; Merck, Amsterdam) in five different plasma samples over the concentration range of 10-100 pg ml-'. The average protein binding (k S.D.) in each volunteer for each sulfonamide were calculated.

Renal clearance (Cl,) The apparent and true renal clearance values of sulfatroxazole and its

metabolites were calculated from the average renal excretion rate in each urine sample, divided by the plasma concentration at the midpoint of the measured time interval. For the calculation of the apparent renal clearance values, the total plasma concentration was used; for the 'true' renal clearance values, the free or unbound plasma concentration was used.

Acetylator phenotype

sulfadimidine as described earlier.9 Volunteers were phenotyped according to their ability to acetylate

Statistics Regression lines, standard deviations, and Student's t-test were calculated

according to standard statistical procedures with an HP 41 calculator (Hewlett Packard). Curve fitting and calculation of the rate constants for metabolism and renal excretion were carried out by means of NONLIN' according to the model shown in Figure 2. The intrinsic half-life of the parent drug and metabolites are calculated from the elimination (metabolic + renal) rate constants.

kabs.

1 1 kac. 1 kr SOH krs k r N L

Figure 2. The pharrnacokinetic model of sulfatroxazole

Tab

le 1

. So

me

phar

mac

okin

etic

par

amet

ers

of s

ulfa

troxa

zole

Prot

ein

bind

ing

Subj

ect

Dos

e TI

,? S

TI

,? S

OH

N

4 96

E S

%E

SO

H

%E

N,

%S

%

SO

H

%N

j m

g h

h h

2 r;; E M

.V.

409

22

22

n.d.

9.

1 78

.7

13.2

84

.1 k 6

.3

34.0

f 4

.6

n.d.

X

A.M

.B.

755

13

13

13

12

4

65.1

18

.7

80.1

k 2

.6

37.1

f 6

.6

79.6

k 1

.7

5 Y

.A.H

. 77

4 26

26

26

5.

4 70

.1

23.0

85

.5 k

1.2

43

-1 k

9.1

80

.3 +

_ 2.

7

T.J

. 70

6 30

30

30

7.

8 73

.6

19.2

83

.5 k

3.8

25

.4 f 4

.0

81.9

k 1

.5

& T

.V.

833

26

26

26

10.8

71

.7

16.9

81

.1 k 5

.1

37.3

k 1

.5

80.2

5 6

.0

p J.

V.

486

18

18

n.d.

7.

2 83

.2

10.3

87

.9 ?

1.6

49

.4 k

1.7

n.

d.

m

J.N

.*

758

24

n.m

24

8.

9 n.

m.

17.1

B

.W.*

73

5 20

n.

m.

28

10.6

n.

m.

11.8

82

.0 k 3

.0

n.m

. 80

.5 k

1.5

2 $ > 8

Mea

n 9.

2 k 2

.2

73.7

f 6

.4

16.4

k 4

.0

83.9

k 2

.5

37.7

k 8

.1

81.0

k 1

.7

E T

.V.

856

20

20

20

10.9

81

.3

13.6

81

.1 2

5.1

37.4

k 1

.5

80.2

k 6

.0

z +p

robe

neci

d 2.

5g

30

30

30

91.7

k 7

.1

31.5

k 4

.5

81.9

k 2

.0

m 2 2

86

4 k

3.0

n.

m.

80.2

? 0

.1

T.V

.*

617

26

n.m

. 26

10

.7

n.m

. 17

.0

84.8

k 1

.7

n.m

. 84

.4 5

1.3

N4-

acet

ylsu

lfatro

xazo

le

T.V

. 56

2 28

n.

d.

4.5

2 2

8 1.

1 n.

d.

92.8

n.

d.

n.d.

86

.1 k

0.7

*Pilo

t stu

dy.

S: su

lfat

roxa

zole

. N4:

N,-a

cety

sulf

atro

xazo

le.

SOH

: 5-hydroxysulfatroxazole. S

bE: p

erce

ntag

e of

the

dos

e ex

cret

ed i

n ur

ine

n.d.

: not

det

ecta

ble.

n.r

n.:

not

mea

sure

d.

N

P

w

244 T. B . VREE E T A L .

:

-

RESULTS

Sulfatroxazole Figure 3 shows the plasma concentration-time curves and renal excretion

rate-time profiles of sulfatroxazole and its metabolites, 5-hydroxy- and N4-acetylsulfatroxazole, in a volunteer after an oral dose of 774mg. The half-lives of the parent drug and its two metabolites are 22 h.

Hydroxylation is the main metabolic pathway, as 70 per cent of the dose is excreted in the urine as 5-hydroxysulfatroxazole and 23 per cent as the acetylated metabolite, N4-acetylsulfatroxazole. Similar data are found in all subjects and are summarized in Table 1. The average protein binding for sulfatroxazole and N4-acetylsulfatroxazole in all subjects is 83.9 k 2.5 per cent and 81.0 f 1-7 per cent respectively, while that for 5- hydroxysulfatroxazole is considerably lower, 37.7 k 8.1 per cent.

The renal clearance of sulfatroxazole is low and varies between 3 and 14ml min-l (mean 4.9 k 4.7ml min-I). The renal clearance values for the acetyl-

renal excr. rate rrg/min

,.Ji"*i? 774rng sulfatroxazole '7 --y ?*

I - 1 I I I I I 1 I 0 LO 80 140 160 h

Figure 3. Plasma concentration-time curves and renal excretion rate-time profiles of sulfatroxazole (S) and its metabolites 5-hydroxysulfatroxazole (SOH) and N,- acetylsulfatroxazole (N4) in a subject after an oral dose of 774 mg of sulfatroxazole. The half-lives

of all compounds are 22 h and there is a complete mass balance

Tab

le 2

. R

enal

cle

aran

ce v

alue

s of

sul

fatr

oxaz

ole

and

its m

etab

olite

s

Dos

e CI

, Sf

C1,

SOH

f c1

, N4f

Uri

ne f

low

U

rine

pH

Su

bjec

t m

g m

l min

-' f S

.D.

ml m

in-'

4 S

.D.

ml m

in-'

4 S

.D.

ml m

in-'

k S

.D.

4 S

.D.

A.M

.B.

755

Y.A

.H.

774

M.V

. 40

9 T

.J.

706

T.V

. 83

3 J.

V.

478

B.W

.*

735

J.N

.*

758

T.V

.*

617

T.V

. 85

6 + p

robe

neci

d 2.

5 g

N4-

acet

ylsu

lfatr

oxaz

ole

T.V

. 56

2

7.10

f 5

.68

3.68

rt 3

.55

13.6

5 f 1

3.1

3.06

f 2

.23

3.16

f 2

.92

14-3

8 k 1

1.0

5.66

f

2.94

7.

28 f

5.28

7.

70 rt

4.05

1.

37 f

0.59

2.

49 k

1.

57

7.70

rt

5.60

222

4

43

129 f

33

158

4

86

105 f

25

90 f

18

400

rt 16

3 n.

m.

n.m

. n.

m.

105 f 2

5 75

rt

12

n.d.

286

k

68

210 f

35

n.d.

17

5 f

34

136 f

24

n.d.

11

2 f

40

153 f

33

239

k

39

184

k

46

96 f

20

343 f 1

32

2.60

f 2

.45

0.60

f 0

.25

1.09

f 0

.58

2-21

4 1

.56

1.33

f 1

.02

2.50

f 1

.13

1.83

f 1

.08

1.17

4 0

-51

1-65

f 1

.09

2.20

k 1

.96

34

0 k 2

.71

3.25

f 2

.76

6.17

f 0

-59

5.54

f 0

.25

5.96

f 0

.67

5.51

k 0

.47

5.90

4 0

.60

5.94

f 0

-97

6.66

rt 0

-66

6.36

k 0

.51

6.36

f 0

.67

6.36

k 0

.82

7.26

k 1

.10

7.26

f 0

.27

*Pilo

t stu

dy.

CI,:

ren

al c

lear

ance

, f:

cal

cula

ted

on p

rote

in f

ree

plas

ma

conc

entr

atio

n, S

: su

lfatr

oxaz

ole,

SO

H: 5-hydroxysulfatroxazole, N

4:

N4-acetylsulfatroxazole, n.

d.:

not

dete

ctab

le,

n.m

.: n

ot m

easu

red.

N

P

o\

Tab

le 3

. R

ate

cons

tant

s of

ac

etyl

atio

n, d

eace

tyla

tion,

hyd

roxy

latio

n, o

f re

nal

excr

etio

n an

d vo

lum

es o

f di

stri

butio

n of

su

lfat

roxa

zole

(S)

. 5-h

ydro

xysu

lfatro

xazo

le (

SOH

) and

N4-

acet

ylsu

lfatro

xazo

le (N

,)

k, S

OH

k, N

4 h-

1 h-

1 VS

1

vSO

H

I VN

, 1

A.M

.B.f

0-01

8 0.

32

0.05

3 Y

.A.H

.f

0.01

8 0.

31

0.03

3 M

.V.

f 0.

090

0.12

0.

036

0.05

3 0.

63

0.13

8.

5 7.

0 23

.3

0.00

16

0.41

0.

048

11.5

13

.1

49.2

0.

0045

0.

20

0.02

7 16

.6

31.5

8.

6

0.04

2 f 0

.042

0.

26 k

0.1

1 0.

041

k 0

.017

M

ean

0.20

< p

< 0

.25

0.40

< p

< 0

.45

0.01

25 <

p <

0.0

25

T.J

. s

0.00

92

0.00

056

0.01

3 0.

0014

0.

20

0.20

13

.4

21.3

8.

5 T

.V.

s 0.

028

0.57

0.

022

0.00

26

0.29

0.

11

10.4

12

.0

14.6

J.

V.

s 0.

021

0.03

2 0.

019

0.00

11

0.16

0.

21

40.1

85

.4

10.7

Mea

n 0.

020 f 0

.010

0.

20 f 0

.32

0.01

8 ?

0.0

05

f: ‘

fast

’ ace

tyla

tor,

s: ‘

slow

’ ac

etyl

ator

.

Tab

le 4

. In

trin

sic

and

obse

rved

hal

f-liv

es o

f su

lfat

roxa

zole

and

its

met

abol

ites

calc

ulat

ed b

y N

ON

LIN

Ace

tyla

tor

Intr

insi

c ha

lf-lif

e O

bser

ved

TI,,

R

atio

El

imin

atio

n ra

te g

over

ning

Su

bjec

t ph

enot

ype

S S

OH

N

4 S

ace

: dea

c : hy

drox

pr

oces

ses

A.M

.B.

fast

9.

05

1.53

1.

10

13.0

1

:18

: 3

rena

l ex

cret

ion

S + h

ydro

xyla

tion

Y.A

.H.

fast

13

.0

1.94

1.

69

26.0

1

:17

: 2

rena

l exc

retio

n S

+ hyd

roxy

latio

n M

.V.

fast

5.

30

4.60

3.

50

22.0

3

:3

: 1

re

nal

excr

etio

n S

+ hyd

roxy

latio

n T

.J.

slow

29

.7

3.50

3.

50

30.0

16

:

1

: 23

ren

al e

xcr.

+ ac

etyl

atio

n S

+ hyd

roxy

latio

n T

.V.

slow

13

.2

1.02

2.

41

26.0

1

:26

: 1

rena

l ex

cret

ion

S + h

ydro

xyla

tion

J.V

sl

ow

16.6

2.

84

4.45

18

.0

1 :

1.5

: 1

rena

l ex

cr. +

acet

ylat

ion

S +

hydr

oxyl

atio

n

S: s

ulfa

trox

azol

e, S

OH

: 5-hydroxyrnethylsulfatroxazole, N4: N

,-acetylsulfatroxazole,

ace:

ace

tyla

tion,

dea

c: d

eace

tyla

tion,

hy

drox

: hy

drox

ylat

ion.

248 T. 0. VREE E T A L .

and hydroxy metabolites are high and vary between 112 and 239ml min-' (mean 186 k 60ml min-') for the N4-acetyl metabolite and between 90 and 400 ml min-' for 5-hydroxysulfatroxazole (mean 184 f 116 ml min-I). The individual renal clearance values of all subjects are summarized in Table 2.

Metabolic rates The rates of hydroxylation, acetylation and deacetylation were calculated

by means of NONLIN, according to the pharmacokinetic model shown in Figure 2. The rate constants (h-I) are given in Table 3.

Table 4 summarizes intrinsic half-lives of sulfatroxazole and its two metabolites and the observed half-life of the parent compound. The ratios between acetylation, deacetylation and hydroxylation and the rate limiting processes in the elimination of sulfatroxazole are given in Table 4.

Phenotyping In Table 3, the subjects are arranged according to their known acetylator

phenotype. Acetylator phenotype did not influence the rates of acetylation and deacetylation, while the rate of hydroxylation was significantly higher (0.0125 < p < 0.025) in 'fast' acetylators than in 'slow' acetylators.

Probenecid co-medication Figure 4 shows the effect of probenecid on the renal excretion of

5-hydroxy- and of N4-acetylsulfatroxazole. Probenecid significantly lowers the renal clearance of 5-hydroxy- and N4-acetylsulfatroxazole as shown in Table 2. Probenecid increases the of all compounds from 20 to 30 h as shown in Figure 4. The renal clearance value of N4-acetylsulfatroxazole is reduced from 184 f 46ml min-' in the 24h preceeding probenecid co-medication to 96 f 20ml min-' after probenecid administration (p < 0-0005). Probenecid reduces the renal clearance of 5-hydroxysulfatroxazole from 104 k 25 ml min-' to 75 k 12 ml min-' (p < 0.0005).

Probenecid decreases the protein binding of 5-hydroxysulfatroxazole from 37.3 k 1.5 per cent to 31.5 f 4.5 (p < 0-0005), increases the protein binding of sulfatroxazole from 81.5 f 5-1 to 91.7 +_ 7.1 per cent (p < 0-05), but did not change the binding of N4-acetylsulfatroxazole (80.2 & 6.0 per cent versus 81.9 If: 2.0 per cent; p = 0.5).

N4-acetylsulfatroxazole Figure 5 shows the pharmacokinetic profile of N4-acetylsulfatroxazole and

its metabolite sulfatroxazole in a volunteer after an oral dose of 562 mg. N4-acetylsulfatroxazole is almost entirely (92.8 per cent) and rapidly ( T1/2

4.5 h) excreted unchanged, 1.1 per cent is deacetylated to sulfatroxazole. No hydroxylation of N4-acetylsulfatroxazole could be observed. The plasma concentration-time curve of N4-acetylsulfatroxazole shows the biphasic elimination curve due to the acetylation-deacetylation equilibrium.

SULFATROXAZOLE PHARMACOKINETICS 249

1

1 I I I I I I I 1 0 LO 80 120 1 6 O h

Figure 4. The effect of probenecid (2.5 g) co-medication on the plasma concentration-time curves of sulfatroxazole (S) and its metabolites 5-hydroxysulfatroxazole (SOH) and N,- acetylsulfatroxazole (N.,). The renal clearance of both metabolites is reduced by probenecid (P)

DISCUSSION

Sulfatroxazole, the 4-methyl substituted structural analogue of sulfamethox- azole, shows metabolic and pharmacokinetic behaviour that differs radically from that of sulfamethoxazole. While sulfamethoxazole is primarily acerylated (60-70 per cent), the predominant metabolic pathway of sulfatroxazole is hydroxylation (70 per cent). Hydroxylation of sulfatroxazole and sulfamethoxazole takes place at the same (5-methyl) group. l 7 Hydroxyla- tion of N4-acetylsulfatroxazole did not take place (the compound N4-acetyl-5- hydroxysulfatroxazole is not detected), while 10 per cent of sulfamethoxazole is acetylated and hydroxylated. I4-l7

Sulfatroxazole is not the only sulfonamide susceptible to hydroxylation. The structural analogue sulfamoxole (2-sulfanilamido-4,5-dimethyloxazoyl) shows a comparable behaviour. Of the administered dose, 10 per cent is

250 T. B . VREE ET A L .

plasma conc.ug/ml renal excr. rate pglrnin

1000 1

Figure 5 . Plasma concentration-time curves and renal excretion rate-time profiles of N,-acetylsulfatroxazole (N4) and its metabolite sulfatroxazole (S) in a subject after an oral dose

of 562 mg of N,-acetylsulfatroxazole

excreted in the urine as parent drug and 15 per cent as N4-acetylsulfamoxole while 75 per cent can be ascribed to hydroxylation."

The rate governing processes in the elimination of sulfatroxazole are hydroxylation and renal excretion in 4 out of 6 subjects. In these 4 subjects ( 3 'fast' and 1 'slow' acetylator), the rate of deacetylation is 3-26 times higher

SULFATROXAZOLE PHARMACOKINETICS 25 1

than the rate of acetylation, reducing the importance of the acetylation process. In 2 subjects (out of 6, and both 'slow' acetylators), acetylation is of the same order or faster than that for deacetylation. In these 2 subjects (members of one family), acetylation also governs the elimination. The rate constants and the ratios between these constants, calculated from the metabolic processes, are different in each subject and seem to be subject (genes-enzymes) dependent.

The subjects in Table 3 are arranged according to their known acetylator phenotype. When the metabolic rate constants of these two groups of subjects ('fast'-'slow' acetylators of sulfadimidine) are compared, the acetylation and deacetylation rate constants were not different (0.20 < p < 0.25, respectively, 0.40 < p < 0-45). This finding is understandable as the rate of hydroxylation and the renal clearance of sulfatroxazole are the principle processes in the elimination. The rate of hydroxylation of sulfatroxazole is significantly faster (1.4 times; 0.0125 < p < 0.025) in 'fast' acetylators than in 'slow' acetylators.

The parallelism in the plasma concentration-time curves of sulfatroxazole and its two metabolites indicates that the intrinsic half-life of the metabolites is much shorter than that of the parent drug, as is demonstrated in Table 4. This short intrinsic half-life of the metabolites is caused by their high renal clearance values. The difference between the intrinsic half-life of sulfatrox- azole and its observed half-life results from the contribution of deacetylation of N4-acetylsulfatroxazole to the plasma concentration of sulfatroxazole. The greatest difference between the two half-lives is seen in those subjects with the highest deacetylation/acetylation ratio.

The renal clearance of sulfatroxazole is low and depends on the variables urine flow and urine pH. The renal clearance of 5-hydroxysulfatroxazole is high (184 -t 116ml min-') and equals that of N4-acetylsulfatroxazole (186 k 60 ml min-'). This high renal clearance indicates that active tubular secretion is involved in the renal clearance of both metabolites as is demonstrated by the co-medication of probenecid. Tubular reabsorption will be a relatively minor process as no urine flow and pH dependency is observed.

Probenecid co-medication (2.5 g) lowers the renal clearance of 5- hydroxysulfatroxazole from 105 -t 25ml min-' to 75 f 12ml min-' (p < 0-0005) and that of N4-acetylsulfatroxazole from 184 k 46ml min-' to 96 k 20 ml min-' (p < 0.0005). Probenecid does not effect the renal clearances of sulfatroxazole (0.15 < p < 0.20) or creatinine (0.10 < p < 0.15).

From the kinetic viewpoint, sulfatroxazole may be a suitable sulfonamide for general practice, allowing a dosage regimen of one daily administration. " The low acetylation rate and low renal clearance indicate a low percentage of loss of microbiologically active compound. 5-Hydroxysulfatroxazole, in which the para-amino phenyl group is available for interaction during PABA synthesis in bacteria, shows an activity of 5 per cent of the ~ a r e n t . ~ " ~ The low renal clearance of sulfatroxazole makes the compound unsuitable for the treatment of urinary tract infections. The high plasma concentration and the

252 T. B. VREE E T A L .

presumable high tissue concentrations may make the compound useful for the treatment of systemic infections.

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