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 N 4 -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 sulphamethox- azole 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 ex- tent 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 antibac- terial chemotherapy alone or in combination with tri- methoprim (co-trimoxazole). Sulphamethoxazole ex- erts its chemotherapeutic effect by antagonism of para aminobenzoic acid in the bacterial synthesis of folic acid, but the metabolite N 4 -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 meta- bolite (Kaplan and Abruzzo, 1976). Analytical determination of sulphonamides in pharmacokinetic studies and in routine clinical in- vestigation is generally carried out by a spectro- photometric 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 con- centrations of the parent drug and metabolite can be measured over a wide concentration range, including therapeutic and very low concentrations of sulpha- methoxazole and its metabolites (O.5pg/ ml to

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Page 1: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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

Page 2: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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.

Page 3: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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).

Page 4: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

-- . 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).

Page 5: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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.

Page 6: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

r

Pharmacokinetics of Sulphamethoxazole in Man

c: ! ]

Q)

" c ~

'" Q)

"0 co c Q)

a:

2

••• •

y;0678x-0200 r ;0.96

Urine pH 5.29 !0.35

Sub) AMB

• •

. I.

Urine flow Iml/min)

4r-------------------------------~

1.0

30

20

• c: E ..... ] 10 •

Q)

" c •• ~ III • oS! .. " co c Q)

ex::

• •

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.

Page 7: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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).

Page 8: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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

Page 9: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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.

Page 10: Pharmacokinetics of Sulphamethoxazole in Man: Effects of Urinary pH and Urine Flow on Metabolism and Renal Excretion of Sulphamethoxazole and its Metabolite N4-Acetylsulphamethoxazole

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.

References

Avery. G.S.: Drug data information; in Drug Treatment. Appen­dix A p.892. (ADIS Press. Sydney; Churchill Livingstone. Edinburgh; Lea & Febiger. Philadelphia 1976).

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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).