pharmacokinetics of sulphamethoxazole in man: effects of urinary ph and urine flow on metabolism and...
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Summary
Clinical Pharmacokinetics 3: 319-329 (1978) © ADIS Press (1978)
Original Article
Pharmacokinetics of Sulphamethoxazole in Man:
Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsutphamethoxazole
T.B. Vree, YA. Hekster, A.M. Baars, J.E. Damsma and E. van derKleijn
Department of Clinical Pharmacy. Sint Radboud Hospital. University of Nijmegen. Nijmegen
A high performance liquid chromatography methodfor the determination of sulphamethoxazole and its metabolite N.-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH. the renal excretion rate and the renal clearance [)f sulphamethoxazole is dependent on the urine flow. The renal clearance [)f the metabolite N. -acetylsulphamethoxazole is not influenced by urinary pH or urine flow.
No clear acetylator phenotype could be detected in the group [)f volunteers studied. The extent of acetylation depends on the amount [)f sulphamethoxazole available for acetylation. thus indirectly on the urine pH and flow.
Sulphamethoxazole is available for use in antibacterial chemotherapy alone or in combination with trimethoprim (co-trimoxazole). Sulphamethoxazole exerts its chemotherapeutic effect by antagonism of para aminobenzoic acid in the bacterial synthesis of folic acid, but the metabolite N4-acetylsulphamethoxazole has no effect on bacterial growth (Gallien, 1973; Gower and Tasker, 1976; Hills et ai., 1976; Hughes et ai., 1975; Lau and Young, 1976; Smellie et ai., 1976). Sulphamethoxazole is eliminated from the body through metabolism by acetylation in the liver and by renal excretion of the parent drug and metabolite (Kaplan and Abruzzo, 1976).
Analytical determination of sulphonamides in pharmacokinetic studies and in routine clinical investigation is generally carried out by a spectrophotometric method, based on the one originally described for sulphanilamide by Bratton and Marshall (] 939) and modified by Rieder (] 972). For the purpose of this study, a method involving high performance liquid chromatography was developed (Vree et ai., 1977). With this method, plasma concentrations of the parent drug and metabolite can be measured over a wide concentration range, including therapeutic and very low concentrations of sulphamethoxazole and its metabolites (O.5pg/ ml to
Pharmacokinetics "of SulphamE1thoxazpLe. in. Man
1 OOOJ.lgl mI). The method allows the determination of pharmacokinetic properties such as renal clearance in each urine fraction. The influence of. a number of variables, such as urine flow and urine pH, on renal' excretion rate can be investigated.
In general the renal excretion rate of a drug may depend on the pKa of the drug, the pH of the urine, and urine flow. As sulphamethoxazole is an acidic drug with pKa 5.7 (Avery, 1976) it may be assumed that the renal excretion rate is dependent on urinary pH (Braunlich and Splinter, 1976; Dettli et aI., 1967; Kostenbauder et aI., 1962). The aim of this investigation was to see whether changes in urinary pH and variation in urine flow influence the renal excretion of sulphamethoxazole and its metaboliteN4-acetylsulphamethoxazole, 'and perhaps acetylation of the parent compound;
Materials and Methods
Apparatus
320
Drugs
Sulphamethoxazole and N4-acetylsulphamethoxazole were obtained from Hoffman La Roche (Mijdrecht, The Netherlands) through the courtesy of Dr J. Kuitert. Both compounds were 100 % pure according to the HPLC chromatogram.
Subjects
Ten healthy caucasian subjects, all employees of the Department of Clinical Pharmacy, volunteered for this study. Sulphamethoxazole was administered in doses of 800, 400, 200 and 100mg powder in a gelatine capsule. The drug was taken orally 1.5 hours after a standard breakfast.
Blood samples of 0.2ml were collected at scheduled intervals by fingertip puncture (Microlance No. 433, Becton Dickinson). Spontaneously voided urine was collected for 56 hours. The urine was maintained alkaline (pH 7 to 8) by the regular intake of 109 of sodium bicarbonate per day. An acidic urine (pH 5 to 6) was achieved' by the intake of8g ·of·am- -monium chloride per day.
A Spectra Physics 3500B high performance liquid chromatograph (HPLC) equipped with a spectrophotometric detector (model 770) was used. The
- --detector-wasconiieCted -toaTmVrecOi'der-(BD -7-;-- - -'-' --- "~-- -. --- -.-.-. - ------
Kipp and Sons, Delft, The Netherlands). A stainless steel column, 15cm long and 4.6mm id packed with Lichrosorb RP8, particle size 5J.lm, was obtained from Chrompack (Middelburg, The Netherlands). An injection loop. of 100J.lI was used. Detection of sulphonamides was performed at 260nm, the detection limit being 0.5J.lg/ml.
Solvents
The solvent was a mixture of phosphate buffer and methanol of pH 6.7 (390ml of 0.067 M KH zP04 was mixed withlOml of 0.067 M NazHP04 and 80ml of methanol). The solvent flow rate was 1.6ml/min at a pressure of II 5atm.
Sample Preparation
Serum: The serum was diluted in I in 10 with distilled water. To 0.2ml of the diluted serum 0.8ml of perchloric acid (0.33N) was added. The solution was thoroughly mixed on a Vortex mixer and subsequently allowed to stand for 10 minutes. After centrifugation at 4000 rpm for 5 minutes, 100J.lI of the supernatant was injected onto the column. A calibration curve was made by adding known concentrations of sulphamethoxazole to the drug-free serum. Once a calibration curve had been made, 3 standards were included with each series of determinations in order to check column stability.
Urine: 0.5ml ofperchloric acid (0.33N) was added to 10J.lI of urine. The solution was mixed and 100J.lI injected onto the column.
Pharmacokinetics of 5ulphamethoxazole in Man
Recovery of sulphamethoxazole added to human serum in the concentration range of I to 200).1g/ ml was 88 % ± 4 SD. If serum is not diluted the recovery of sulphamethoxazole after deproteinisation is less (80% ± 7 SD). The recovery of sulphamethoxazole added to urine was 100 % ± 2 SD.
Renal Clearance
The renal clearance was calculated as follows: the renal excretion rate dQ/ dt ().1g/ min) is proportional to the plasma concentration CA ().1g/mJ), by the proportionality constant Kr, being the renal clearance (mil min). For the calculation of Kr the average renal excretion rate was divided by the mean plasma concentration during the measured time interval. From
10
,; i •
o Hours
10
L---------l ., I..-.-~-.
'L5_~~
Urine pH 5.5-6.0 800mg p.o . Subj. YAH
20 30 40
NAcS'
50 60
321
each urine and the corresponding plasma sample the renal clearance constant was calculated.
Results
Effect of Urinary pH on the Percentage of Renal Excretion, Half-life and Absorption Rate
Figure I shows the effect of urinary pH on the renal excretion rate of sulphamethoxazole and N4-
acetylsulphamethoxazole in the same volunteer at acid and alkaline pH. Under acidic urine conditions (pH < 5.5 to 6.0) sulphamethoxazole was strongly reabsorbed; the net percentage of the compound excreted unchanged being less than 10%, whilst 40 to 50 % of the dose was excreted as N4-
10
o 10 Hours
....---1
~"L ___ '_"
~-0 __ '_t1/2 9ti
Urine pH 7.5-8.5 800mg p.o. Subj. YAH
20 30
-- --
40
1-_;
50
36%
5
NAcS
60
Fig. 1. Plasma concentration (~g/mn and renal excretion rate (~g/min) of sulphamethoxazole (5) and its metabolite N.acetylsulphamethoxazole (NAcS) under conditions of acidic (left) and alkaline (right) urine in the same volunteer who took 800mg
of sulphamethoxazole orally. Note that with acidic urine only 9.5% sulphamethoxazole was excreted unchanged while this amount increased to 36% with
alkaline urine. The elimination half-life of sulphamethoxazole with acidic urine is slightly higher (t1/2 l1h) than with alkaline urine (t1/29h).
-- . Pharmacokinetics ofSulphamethoxazole.in Man_~ ___ < __ 322
Table I. Renal excretion of sulphamethoxazole and its metabolite N.-acetylsulphamethoxazole. Influence of urinary pH and urinary flow. Time course of elimination 60h
Subject Sex Dose (mg)
JDE2 F 100 JED F 100 YAH2 M 100 JRK2 F 100 YAH2 M 200 TBV2 M 200 FH' F 200 ET M 200 TL F 200 PJMG' M 200 YAH' M 800
AMB' F 400 JRK F 200 YAH2 M 800 JRK F 100 FH F 200 JED F 200 AMB' F 400
1 F~st acetylator of procainamide. 2 Slow acetylator of procainamide.
Urine pH Urine flow Excretion (% of dose)3 (ml/min)
smz asmz
7.23 ±0.46 1.84 ± 1.10 38 48 7.41 ± 0.47 4.50 ± 3.06 32 31 7.33 ± 0.38 0.86 ± 0.30 33 52 7.73 ± 0.35 1.23 ± 0.83 37 67 7.02 ± 0.60 0.87 ± 0.42 23 45 7.10 ± 0.51 1.19 ± 0.76 22 47 7.20 ± 0.56 1.01_± 0.94 29 72 7.29 ± 0.55 1.37 ± 0.80 33 35 7.42 ± 0.48 2.77 ± 3.33 33 42 7.33 ± 0.44 2.82 ± 2.04 43 56 7.01 ± ·0.39 0.80 ± 0.37 36 67
6.46 ± 0.78 1.90 ± 1.89 24 35 6.35 ± 0.66 2.11 ± 1.76 26 24 5.77 ± 0.32 1.56 ± 1.22 9.5 52 5.90 ± 0.37 0.90 ± 0.35 8.3 40 5.73 ± 0.94 0.65 ± 0.18 31 37 5.71 ± 0.58 1.71 ± 2.12 15 36 5.36 ± 0.46 2.27 ± 1.68 3.4 40
3 SMZ = sulphamethoxazole; ASMZ = N.-acetylsulphamethoxazole.
---- -----;-- ---~- -------.... -acetylsulphamethoxazole (table I). When the urine was maintained alkaline (pH 7 to 8), about 30 to 40 % of sulphamethoxazole was excreted unchanged and 40 to 70 % of the dose excreted as N4-acetylsulphamethoxazole (table I). The percentage of sulphamethoxazole excreted unchanged under uncontrolled urinary pH conditions ranged between 30 and 40%.
One volunteer (Y AH) took the same dose of sulphamethoxazole under the 2 extremes of pH. Differences in the plasma (elimination) half-life of sulphamethoxazole under alkaline and acidic conditions were small (t I /2 acidic 11 h; t 1/2 alkaline 9h). The 2 extremes of urinary pH also had some influence on the absorption rate of sulphamethoxazole. Under alkaline urine conditions the compound was absorbed faster. The maximum plasma concentration
of sulphamethoxazole was reached 1 hour after oral intake under alkaline conditions, while it was 3 hours under acidic conditions. As a result, the maximum plasma concentration of the metabolite (fig. 2) is reached earlier under alkaline urine conditions (9h) than under acidic conditions (t 1 h). The renal excretion rate is higher under alkaline urine conditions (450)Jg/min) than under acidic conditions (350)Jg/min), while the percentage of the metabolite excreted under alkaline conditions (68 %) is also higher than under acidic urine conditions (52 %). Due to
. the suppressed renal excretion of sulphamethoxazole, the maximum plasma concentration of the metabolite is higher (9)Jg/ml) under acidic than under alkaline urine conditions (6.5)Jg/mJ), whilst the elimination half-life of the metabolite is longer (t I h) under acidic than under alkaline urine conditions (9h).
Pharmacokinetics of Sulphamethoxazole in Man
100
E -'" 2-c o
10
'';:; 1
~ c
" " c. o " co E " co 0:
__ 0 ____ td;.2 llh .,..,...-,,- .. ---
o%,96-- o--"'O-o-"--e- - ---
-I --- f""--f
! - -- --- ~~~h --. I P ... 0 ....
, p
, ~ 0:::0 Urine pH 5-6 t'I211h
" ~ , , 6
Hours
10
Urine pH 7-8 t'I29h Sulphamethoxazole
N.-Acetylsulphamethoxazole
Subj. YAH
'5 20 25 30
Fig. 2. Plasma concentration of sulphamethoxazole and its metabolite after oral administration of BOOmg at alkaline (0--0) and acidic (0--0) urine.
Absorption with alkaline urine is somewhat slower than with acidic urine. The maximum plasma concentration of N.acetylsulphamethoxazole is reached faster with acidic urine, which may be explained by the observation that sulphamethoxazole is absorbed faster with acidic urine and that over the same time course more sulphamethoxazole is available for acetylation.
Renal Clearance versus Urinary pH
Figure 3 shows the linear relationship between the urinary pH and the calculated Kr values of sulphamethoxazole in I volunteer (r = 0.84). Whilst the urinary flow fluctuated in the same time, no significant relationship between flow and Kr value could be detected, even with a variable urine pH (r = 0.15). No obvious relationship (r = 0.25) between urinary pH and Kr could be detected for N4-acetylsulphamethoxazole.
323
Renal Clearance versus Urinary Flow at Constant Urinary pH
When the urine was maintained strictly acidic or alkaline, a linear relationship between urine flow and renal clearance of sulphamethoxazole could be observed in each case. Figure 4 shows the relationship between the renal clearance and urine flow with acidic urine (pH 5.29 ± 0.35) and figure 5 the relationship between renal clearance and urine flow with alkaline urine(pH 7.01 ± 0.39). The renal clearance was I 0 times higher with alkaline urine than with acidic urine. No obvious relationship between the renal clearance and urine flow could be observed for N4-acetylsulphamethoxazole, with either acidic or alkaline urine. An example of this particular behaviour of the parent compound and metabolite is given for acidic urine in figure 6.
20
15
10
5 6
Urine pH
y=-21.51.1..17x r= 0.81.
o 0
9
Fig. 3. Renal clearance of sulphamethoxazole versus urinary pH. No such relationship could be found for N.-acetylsulphamethoxazole.
r
Pharmacokinetics of Sulphamethoxazole in Man
c: ! ]
Q)
" c ~
'" Q)
"0 co c Q)
a:
2
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y;0678x-0200 r ;0.96
Urine pH 5.29 !0.35
Sub) AMB
•
• •
. I.
Urine flow Iml/min)
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30
20
• c: E ..... ] 10 •
Q)
" c •• ~ III • oS! .. " co c Q)
ex::
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•
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• •
y;1773x-2.33 r; 0.82
Urine pH 7.01 :0.39
Sub) YAH
3
Urine flow Iml/min)
5L-____________________________ ~
324
Table II. Renal clearance of sulphamethoxazole and N.acetylsulphamethoxazole
Compound pH Ciearance (ml/min)
Sulphamethoxazole 5 0.5-2.5 7 5-25
N.-Acetylsulphamethoxazole 5-7 40-60
The renal clearance ofsulphamethoxazole and N 4-
acetylsulphamethoxazole is summarised in table II.
Dose Dependent Renal Clearance
Figure 7 shows the relationship between urine flow and renal clearance after a small dose (I OOmg) of sulphamethoxazole when the urine was maintained alkaline (pH 7.33 ± 0.38). It suggests that with alkaline urine and a low dose, a linear relationship between renal clearance and urine flow can be observed for sulphamethoxazole (r = 0.68), and for N 4-
acetylsulphamethoxazole (r = 0.50). However, when the same volunteer took 800mg of sulphamethoxazole, only the linear relationship between renal. clearance and urine flow of sulphamethoxazole (r = 0.82) could be observed, with no such relationship for N4-acetylsulphamethoxazole (fig. 8) .
When the data in figures 7 and 8 are superimposed, the renal clearance-urine flow relationship for sulphamethoxazole is identical for both sets of data. It may be concluded that at doses higher than 100mg, there is little or no dependence on urinary pH and uri-
Fig. 4. Renal clearance of sulphamethoxazole versus urine flow at constant and acidic urine (pH 5.29 ± 0.35).
Fig. 5. Renal clearance of sulphamethoxazole versus urine flow at constant and alkaline urine (pH 7.01 ± 0.39).
Note that the renal clearance is much higher than with acidic urine as shown in figure 4.
Pharmacokinetics of Sulphamethoxazole in Man
10
Sulphamethoxazole
2
400mg orally y=0.678x -0.2 r=0.96
3 4 5
Urine flow (ml/min)
325
N.-Acetylsulphamethoxazole
100 400mg orally
2 3 4 5 6
Urine flow (ml/min)
6r-------------------------------------------------------------~
25
20
C 15
'E .......
! 10
" CJ c: E III 5 j1 CJ
Cii c: " IX:
Sulphamethoxazole
0.5 1.0
lOOmg y= 13.18x + 1.10 r=0.68
1.5 2.0
Urine flow (ml/min)
150
N.-Acetylsulphamethoxazole
0.5
100mg y=64.97x +27.20 r=0.50
...
1.0 1.5 2.0
Urine flow (ml/min) 7~ ________________________________________________________________ ~
Fig. 6. Renal clearance of sulphamethoxazole versus urine flow at constant and acidic urine (pH 5.36 ± 0.46) in subject AMB. Note that the renal clearance of N.-acetylsulphamethoxazole is much higher than that of the parent compound, but no rela
tionship between urine flow and renal clearance could be observed for the metabolite.
Fig. 7. Renal clearance versus urine flow with alkaline urine (pH 7.33 ± 0.38) in a volunteer (YAH) who took l00mg of sulphamethoxazole.
In this experiment a relationship between urine flow and renal clearance of the metabolite can be observed; though of low probability (r = 0.50).
Pharma<:okin~tics ~f Sulpharnet~oxazole .!n Man 326
Sulphamethoxazole N.-Acetylsulphamethoxazole
15 150 BOOmg
Fig. 8. Renal clearance versus urine flow in the same volunteer (YAH) as shown in figure 7. who took BOOmg of sulphamethoxazole under alkaline urine conditions (pH 7.01 ± 0.39).
In this experiment. the relationship between urine flow and renal clearance of the metabolite is lost.
nary flow for the renal excretion rate of N4-
.. .a:cetyl§\!lpJlaIlle~!l9J(?Z_ql~·._fQ.r J~14-as:e~yls.,!lpJ!~~~h-_ oxazole, both sets of data are in the same relative range, with a major difference that- after a dose of 800mg of sulphamethoxazole, the renal clearance of the metabolite is within narrower limits than after a dose of 100mg. The limited renal clearance may be caused by the low water solubility ofN4-acetylsulphamethoxazole.
Individual Characteristics of Renal Excretion
The relationship between renal clearance and urine flow with constant alkaline urine for 2 different human volunteers (YAH, male at 800mg and AMB, female at 400mg sulphamethoxazole) appears to be different. Differences in Kr values at almost the same urinary pH and same range of urine flow, may be
caused by differences in reabsorption and excretion
~fficieIlC:Y _qf !~~~Il<!~vid~] .~id_n~r·.T~~r.ea.!>s£l}>ti()~_ efficiency appears to differ, not only between the different volunteers but also in consecutive experiments in the same volunteer.
Influence of Urine Flow and Urinary pH on the Percentage of Acetylation
In the total elimination of sulphamethoxazole, metabolism by acetylation has to compete with renal excretion which is controlled by two main variables: urine flow and urinary pH. When the urine is maintained alkaline or acidic, acetylation and urine flow dominate the elimination process of sulphamethoxazole. However, elimination of N4-acetylsulphamethoxazole is independent of urinary flow and pH. Thus, with alkaline urine, there appears to be
Pharmacokinetics of Sulphamethoxazole in Man
competition between elimination by acetylation and by renal excretion of unchanged sulphamethoxazok The results of the total percentage of the dose of sulphamethoxazole and of the metabolite excreted are given in table I. A linear relationship between the percentage excreted and the urine flow could not be found.
Discussion
Urine flow and particularly urine pH are the two main variables influencing the renal excretion rate and thereby the metabolism of sulphamethoxazole. This is important because of the generally accepted opinion that the genetically controlled acetylator phenotype of sulphonamides (Chapron and Blum,
25
20
Sulphamethoxazole -
o o.
l00mg(e) y= 13.18x + 1.10 r=0.68
1 I . (,
• 1 800mg(O) o· I. y=17.73x-2.33
o / .r= 0.82
0.5 1.0 1.5 2.0 Urine flow (ml/min)
327
1976; Das and Eastwood, 1975; Liscombe and Nicholls, 1976; Rao et aI., 1970; Schroeder and Price Evans, 1972) can be correlated with that of isoniazid (Eidus et aI., 197 J) and procainamide (Gibson et aI., 1975; Karlssonet aI., 1974, 1975; Karlsson and Molin, 1975; Reidenberg et aI., 1975).
Galeazzi et al. (J 976) showed for procainamide that acetylation and renal excretion of the parent compound and metabolite N-acetylprocainamide in man are independent of urine pH and urine flow. These findings were obtained with excretion processes lasting only 24 hours. With rhesus monkeys, preliminary experiments in our laboratory with procainamide revealed that the clearance of procainamide indeed appears to be dependent on urine flow (Vree et aI., 1975). Lima and Jusko (J 978) recently showed in
150
100
c 'E ----]
50 <II
" c: ~
'" <II U c;; c: <II a:
N. -Acetylsulphamethoxazole
00 . 0: 00 . 0
0.5 1.0
l00mg(e) y = 64.97 x + 27.20 r=0.50
~-800mg
1.5 2.0 Urine flow (ml/min)
Fig. 9. Renal clearance of sulphamethoxazole and N.-acetylsulphamethoxazole versus urine flow in the volunteer (YAH) who in separate experiments took 100 and 800mg of sulphamethoxazole under alkaline urine conditions (figs. 7 and 8).
The renal clearance-urine flow relationship of sulphamethoxazole are almost identical for the 2 doses. The renal clearance of N.-acetylsulphamethoxazole is limited and almos~ ~ndependent of the urine flow at the dose of 800mg.
Pharmacokinetics of Sulphamethoxazole in Man
man that the acetylator phenotype of procainamide depends on renal function. Fast and slow acetylators of procainamide participated in this study in an attempt to show a correlation between the acetylation of sulphamethoxazole and procainamide. However, no relationship between the rate and percentage of acetylation of sulphamethoxazole in 'fast' and 'slow' acetylators of procainamide could be discovered in the whole group, who also participated in the procainamide studies (Vree et at, 1975). The 'fast' and 'sloW' acetylators of procainamide proved to be 'unidentified' acetylators of sulphamethoxazole under these standardised conditions.
Acidic urine causes a reduction of the excretion of sulphamethoxazole itself. Table I shows 3 volunteers with a total renal excretion of sulphamethoxazole of less than 10%, which is obtained with acidic urine and slight « 0.5 pH units) variation in pH. When the variation becomes more than 0.50 pH units, the percentage of excreted parent compound increases markedly. The percentage of N4-acetylsulphamethoxazole excreted in the urine under standardised conditions gives no predictive indication of fast or slow acetylation. [Because of the risk of precipitation of N 4-
acetylsulphamethoxazole in the kidney under extreme acidic conditions (Ylitalo and Vapaatalo, 1977), the acidic pH values in this study were restricted to a range from 5.36 to 6.46 (table 1)].
Fast and slow acetylators are generally phenotyped without taking into account urine pH and urine flow (Talseth and Landmark, 1977). Our findings suggest that the metabolism ofsulphamethoxazole by acetylation cannot be correlated with the acetylation of isoniazid and procainamide, as the renal excretion rate of both these compounds is much less dependent on urine pH and flow and thus the rate of acetylation can be easil'y differentiated. Differences in the percentage of N4-acetylsulphonamide derivatives may be accounted for by differences in diurnal variation in urine pH and flow (Dettli and Spring, 1966; Krauer, 1969), or to the existence of different N4-
acetyltransferase enzymes for N-acetYlation of different sulphonamides, as is suggested by McQueen (I 976).
328
Acknowledgements
The authors are grateful to the volunteers J J. Reekers. T. l..enselink. F. Hurkmans. PJ.M. Guelen and E. Termond for participating in this study; to Dr' P. Jordan (Devon Area Health Authority. Department of Pathology. Exeter. England) for his critical remarks during the preparation of the manuscript; and to Dr R. van Dalen. Intensive Care Unit. St. Radboud Hospital. for providing blood samples of the subjects.
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Pharmacokinetics of Sulphamethoxazole in Man
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Author's address: Dr T.D. Vree, Department of Clinical Pharmacy. Sint Radboud Hospital, University of Nijmegen, Niimegen (The Netherlands).