This article was downloaded by: [UAA/APU Consortium Library] On: 16 October 2014, At: 12:00 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Veterinary Quarterly Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tveq20
Pharmacokinetics of sulphamethoxazole in calves and cows a
b
a
J. F. M. Nouws , T. B. Vree , M. Degen & D. Mevius a
RVV‐District 6, P.O. Box 40010, Nijmegen, 6504 AA, The Netherlands b
Clinical Pharmacy , St. Radboud Hospital , Nijmegen, The Netherlands c
Department of Large Animal Medicine, Faculty of Veterinary Medicine , University of Utrecht , Utrecht, The Netherlands Published online: 01 Nov 2011.
To cite this article: J. F. M. Nouws , T. B. Vree , M. Degen & D. Mevius (1991) Pharmacokinetics of sulphamethoxazole in calves and cows, Veterinary Quarterly, 13:1, 10-15, DOI: 10.1080/01652176.1991.9694279 To link to this article: http://dx.doi.org/10.1080/01652176.1991.9694279
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly
c
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Pharmacokinetics of sulphamethoxazole in calves and cows J. F. M. Nouwsl, T. B. Vree2, M. Degenl, and D. Mevius3
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
SUMMARY The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age-dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration-time curves of the N4-acetyl metabolite in the elimination phase were parallel to those of the parent drug; the No-acetyl metabolite plasma percentage depended on age and ranged between 100% (new-born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half-lives: 2.0-4.7 It) and exhibited a relatively small distribution volume ( f/Darea: 0.44-0.571/kg). SMZ was excreted predominantly by glomerular filtration, while its No-acetyl metabolite was actively eliminated by tubular secretion.
INTRODUCTION
Mainly in combination with trimethoprim, sulphamethoxazole (SMZ) has been widely used in human and veterinary medicine since 1969. Many studies have been carried out on its pharmacokinetic behaviour, metabolism and renal clearance in man, in relation to age and disease state, using specific high-performance liquid
chromatography (HPLC) methods (14). In animals, however, this kind of information is limited. The reported elimination half-lives of sulphamethoxazole (SMZ) are varying (2, 4, 5, 7, 8, 11, 12, 13, 14); e.g., in man 9.5 h, in the dog 8 h, in the horse 5 h, in the cow 2.5 h, in the buffalo 7 h, in the pig 3 h, in sheep 2 h and in the cat 10 h. With respect to its metabolism, SMZ is predominantly
acetylated in man, the penguin, the cat and sheep, but in the dog, the homing pigeon, the snail and the water turtle hydroxylation predominates (14, 15, 16, 17, 18).
Sulphamethoxazole/trimethoprim combinations are widely used in veterinary practice, but relatively little is known about the metabolism of SMZ in foodproducing animals. This study deals with the pharmacokinetics, metabolism and renal clearance of SMZ in calves and dairy cows following intravenous administration. MATERIALS AND METHODS
Sulphamethoxazole-20% solution, obtained from Hoffman-La Roche (Mijdrecht, The Netherlands), was administered intravenously to three preruminant calves (aged 4, 7 and 14 days, respectively; dose 15 mg/kg) and to two dairy cows (dose 10 mg/kg; daily milk yield 28 and 34 litres). Blood (and milk) sampling occurred during 48 h and urine sampling during 12 h. SMZ and its metabolites 5-hydroxy-(SOH) and Neacetylsulphamethazole (N4-
SMZ) were analysed by HPLC (14). N4-acetyl and 5-hydroxy metabolite of SMZ were
2 3
RVV-District 6, P.O. Box 40010, 6504 AA Nijmegen, The Netherlands. Clinical Pharmacy, St. Radboud Hospital, Nijmegen, The Netherlands. Department of Large Animal Medicine, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
10
THE VETERINARY QUARTERLY. VOL. 13, No. I, JANUARY 1991
synthesised by Dr. Vree as described previously (14). Protein-binding studies and
deglucuronidation of samples were carried out as described in earlier calculation of pharmacokinetic parameters was performed according papers (9, 10) and to standard procedures (1). RESULTS
Pharmacokinetics (Table 1) Plasma
The plasma sulphamethoxazole (SMZ) concentration-time curves could be Table I.
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
Selected pharmacokinetic data for sulphamethoxazole (SMZ) after a single intravenous administration to three calves and two cows. Animal Age
Calf 1
4 days
Calf 2 7 days
Calf 3 14 days
Cow 1 3 years
15.4
Cow 2 4 years
15.0
14.3
10.0
10.0
31.0 0.70 29.0 4.7 400
23.9 0.74 21.6 4.0 235
41.0 0.93 21.5
30.8
0.75
25.0 0.61
241
155
173
0.099 0.57 0.33 74
0.083 0.46 0.24 49
Dose, mg/kg _
Parameter
A
Units pg/m1
TI/2n
h
Bo
pg/m1
T1/213
h
AUC10101
h.mg/1 h.mg/1
AUCsiAz
CIB(SMZ)
1/kg/h I/kg
VI
1/kg
0.064 0.44 0.25
Na-SMZ/SMZ* _
%
100
VDarca
3.8
232
9.81 2.4
79.0 67.8 0.149 0.52 0.25 24.5
14.8
1.0 76.8 63.2 0.158 0.46 0.25 30.7
SMZ = sulphamethoxazole N4-SMZ = N4-acetylsulphamethoxazole AUCtotai = AUCsiviz + AUCN4-9,1z
* Plasma
percentage of N4-SMZ versus SMZ in the final elimination phase
analysed according to a two-compartment model. In newborn calves the total body clearance (C1B) was less than in adults (30-50%). The distribution volumes (VD,, and VI) in calves and cows were similar. The elimination half-lives were longer in newborn calves than in cows (about 4 h vs. 2 h). The plasma disposition of 1%/IZ and its
Nracetyl metabolite (N4-SMZ) in the newborn calf (no. 1) is illustrated in Figure 1. Milk The
penetration of SMZ into milk h and thereafter decreased parallel was fast. Its concentration peaked within 3 to the SMZ concentration in plasma, the concentration in milk being lower than that in plasma. Figure 2 shows the disposition of
SMZ and N4-SMZ in the plasma and milk of cow 1. The total SMZ and N4-SMZ concentration ratios between milk and plasma were 0.065 and 0.23, respectively; their ultrafiltration concentration ratios were 0.16 and 0.45, respectively.
Metabolism (Tables 1 and 3) The Nracetyl
metabolites was the only metabolite present in plasma, milk and (Figures 1 and 2); no hydroxy and glucuronide derivatives could be detected in plasma, milk and urine. In the newborns N4-SMZ in urine predominated over the parent drug; in the cows the opposite was observed (Table 3). The percentage urine
THE VETERINARY
QUARTERLY. Vol . 13, No. 1, JANUARY 1991
11
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
SMZ
N -S M Z
.0.01 I
0
10
20
1
30
Hours after injection Figure I. Plasma concentration-time curves of sulphamethoxazole (SMZ) and its Mt-acetyl metabolite (/14-SMZ) in a 4-day-old calf following intravenous injection of 15 mg SMZ/kg (t1/2= elimination half-life).
of N4-SMZ in urine and in plasma decreased with age. In the elimination phase of the 4-day-old calf the percentage of N4-SMZ was equal to that of the parent drug (SMZ); in cows 1 and 2 the plasma percentage of N4-SMZ versus SMZ in the elimination phase was 24.5% and 37%, respectively (Table 1). Protein binding (Table 2)
In calves 1 and 2 the plasma protein binding of N4-SMZ was higher than that of SMZ, in calf 3 they were equal and in the cows the protein binding of N4-SMZ was lower. In milk of both cows the protein binding of N4-SMZ and SMZ were 2.4% and 11.6%, respectively. Renal clearance (Table 3)
Both the renal clearance values of SMZ and its Nracetyl metabolite increased with age. In newborn calf no. 1 the renal clearance of N4-SMZ was 12.5 times faster than that of SMZ. Although in the other two calves and two cows the renal clearance rate of N4-SMZ itself was higher than in calf 1, it was relatively lower (only 4.1-5.4 times higher) than of SMZ compared with the 4-day-old calf. The urine pH of the animals was high (pH 7.2-8.9), resulting in a minimal passive tubular reabsorption of SMZ. 12
THE VETERINARY QUARTERLY. VOL, 13, No. 1, JANUARY 1991
100
10
PLASMA M I LK
SMZ
Cs
L_
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
N,SMZ
0 U
0)0 2.4 h 0.1
0.01 1
20
10
0
30
Hours after injection
Figure 2.
Disposition of sulphamethoxazole (SMZ) and its N.racetyl metabolite (N4-SMZ) in plasma and milk of a dairy cow following intravenous administration of 10 mg SMZ/kg (11,2 = elimination half-life). DISCUSSION
Our pharmacokinetic data of SMZ in cows were in agreement with those found by Nielsen and Rasmussen (7). It is noteworthy that for the buffalo an elimination half-time that was three times longer (7 h) was reported (4). The percentage of SMZ and N4-SMZ binding to plasma proteins increased during the first two weeks after birth. The cause of this is the increase of albumen Table 2.
Plasma protein binding of sulphamethoxazole (SMZ) and its MI-acetyl metabolite (N4-SMZ).
Animal Calf 1 Calf 2 Calf 3 Cow I Cow 2
Age
Number of samples
4 days 7 days
6 6
14 days 3 years 4 years
6
6 6
Protein binding (e) SMZ
N4-SMZ
44.9±4.3 48.8±4.0 51.1±2.6 64.0±5.7 64.9±2.6
36.6±4.9* 43.1±3.6
52.6±1.6 52.9±4.6* 49.8±5.2*
Data are expressed as Mean ± SD. * Significantly different from that of SMZ (P
Veterinary Quarterly Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tveq20
Pharmacokinetics of sulphamethoxazole in calves and cows a
b
a
J. F. M. Nouws , T. B. Vree , M. Degen & D. Mevius a
RVV‐District 6, P.O. Box 40010, Nijmegen, 6504 AA, The Netherlands b
Clinical Pharmacy , St. Radboud Hospital , Nijmegen, The Netherlands c
Department of Large Animal Medicine, Faculty of Veterinary Medicine , University of Utrecht , Utrecht, The Netherlands Published online: 01 Nov 2011.
To cite this article: J. F. M. Nouws , T. B. Vree , M. Degen & D. Mevius (1991) Pharmacokinetics of sulphamethoxazole in calves and cows, Veterinary Quarterly, 13:1, 10-15, DOI: 10.1080/01652176.1991.9694279 To link to this article: http://dx.doi.org/10.1080/01652176.1991.9694279
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sublicensing, systematic supply, or distribution in any form to anyone is expressly
c
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Pharmacokinetics of sulphamethoxazole in calves and cows J. F. M. Nouwsl, T. B. Vree2, M. Degenl, and D. Mevius3
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
SUMMARY The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age-dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration-time curves of the N4-acetyl metabolite in the elimination phase were parallel to those of the parent drug; the No-acetyl metabolite plasma percentage depended on age and ranged between 100% (new-born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half-lives: 2.0-4.7 It) and exhibited a relatively small distribution volume ( f/Darea: 0.44-0.571/kg). SMZ was excreted predominantly by glomerular filtration, while its No-acetyl metabolite was actively eliminated by tubular secretion.
INTRODUCTION
Mainly in combination with trimethoprim, sulphamethoxazole (SMZ) has been widely used in human and veterinary medicine since 1969. Many studies have been carried out on its pharmacokinetic behaviour, metabolism and renal clearance in man, in relation to age and disease state, using specific high-performance liquid
chromatography (HPLC) methods (14). In animals, however, this kind of information is limited. The reported elimination half-lives of sulphamethoxazole (SMZ) are varying (2, 4, 5, 7, 8, 11, 12, 13, 14); e.g., in man 9.5 h, in the dog 8 h, in the horse 5 h, in the cow 2.5 h, in the buffalo 7 h, in the pig 3 h, in sheep 2 h and in the cat 10 h. With respect to its metabolism, SMZ is predominantly
acetylated in man, the penguin, the cat and sheep, but in the dog, the homing pigeon, the snail and the water turtle hydroxylation predominates (14, 15, 16, 17, 18).
Sulphamethoxazole/trimethoprim combinations are widely used in veterinary practice, but relatively little is known about the metabolism of SMZ in foodproducing animals. This study deals with the pharmacokinetics, metabolism and renal clearance of SMZ in calves and dairy cows following intravenous administration. MATERIALS AND METHODS
Sulphamethoxazole-20% solution, obtained from Hoffman-La Roche (Mijdrecht, The Netherlands), was administered intravenously to three preruminant calves (aged 4, 7 and 14 days, respectively; dose 15 mg/kg) and to two dairy cows (dose 10 mg/kg; daily milk yield 28 and 34 litres). Blood (and milk) sampling occurred during 48 h and urine sampling during 12 h. SMZ and its metabolites 5-hydroxy-(SOH) and Neacetylsulphamethazole (N4-
SMZ) were analysed by HPLC (14). N4-acetyl and 5-hydroxy metabolite of SMZ were
2 3
RVV-District 6, P.O. Box 40010, 6504 AA Nijmegen, The Netherlands. Clinical Pharmacy, St. Radboud Hospital, Nijmegen, The Netherlands. Department of Large Animal Medicine, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
10
THE VETERINARY QUARTERLY. VOL. 13, No. I, JANUARY 1991
synthesised by Dr. Vree as described previously (14). Protein-binding studies and
deglucuronidation of samples were carried out as described in earlier calculation of pharmacokinetic parameters was performed according papers (9, 10) and to standard procedures (1). RESULTS
Pharmacokinetics (Table 1) Plasma
The plasma sulphamethoxazole (SMZ) concentration-time curves could be Table I.
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
Selected pharmacokinetic data for sulphamethoxazole (SMZ) after a single intravenous administration to three calves and two cows. Animal Age
Calf 1
4 days
Calf 2 7 days
Calf 3 14 days
Cow 1 3 years
15.4
Cow 2 4 years
15.0
14.3
10.0
10.0
31.0 0.70 29.0 4.7 400
23.9 0.74 21.6 4.0 235
41.0 0.93 21.5
30.8
0.75
25.0 0.61
241
155
173
0.099 0.57 0.33 74
0.083 0.46 0.24 49
Dose, mg/kg _
Parameter
A
Units pg/m1
TI/2n
h
Bo
pg/m1
T1/213
h
AUC10101
h.mg/1 h.mg/1
AUCsiAz
CIB(SMZ)
1/kg/h I/kg
VI
1/kg
0.064 0.44 0.25
Na-SMZ/SMZ* _
%
100
VDarca
3.8
232
9.81 2.4
79.0 67.8 0.149 0.52 0.25 24.5
14.8
1.0 76.8 63.2 0.158 0.46 0.25 30.7
SMZ = sulphamethoxazole N4-SMZ = N4-acetylsulphamethoxazole AUCtotai = AUCsiviz + AUCN4-9,1z
* Plasma
percentage of N4-SMZ versus SMZ in the final elimination phase
analysed according to a two-compartment model. In newborn calves the total body clearance (C1B) was less than in adults (30-50%). The distribution volumes (VD,, and VI) in calves and cows were similar. The elimination half-lives were longer in newborn calves than in cows (about 4 h vs. 2 h). The plasma disposition of 1%/IZ and its
Nracetyl metabolite (N4-SMZ) in the newborn calf (no. 1) is illustrated in Figure 1. Milk The
penetration of SMZ into milk h and thereafter decreased parallel was fast. Its concentration peaked within 3 to the SMZ concentration in plasma, the concentration in milk being lower than that in plasma. Figure 2 shows the disposition of
SMZ and N4-SMZ in the plasma and milk of cow 1. The total SMZ and N4-SMZ concentration ratios between milk and plasma were 0.065 and 0.23, respectively; their ultrafiltration concentration ratios were 0.16 and 0.45, respectively.
Metabolism (Tables 1 and 3) The Nracetyl
metabolites was the only metabolite present in plasma, milk and (Figures 1 and 2); no hydroxy and glucuronide derivatives could be detected in plasma, milk and urine. In the newborns N4-SMZ in urine predominated over the parent drug; in the cows the opposite was observed (Table 3). The percentage urine
THE VETERINARY
QUARTERLY. Vol . 13, No. 1, JANUARY 1991
11
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
SMZ
N -S M Z
.0.01 I
0
10
20
1
30
Hours after injection Figure I. Plasma concentration-time curves of sulphamethoxazole (SMZ) and its Mt-acetyl metabolite (/14-SMZ) in a 4-day-old calf following intravenous injection of 15 mg SMZ/kg (t1/2= elimination half-life).
of N4-SMZ in urine and in plasma decreased with age. In the elimination phase of the 4-day-old calf the percentage of N4-SMZ was equal to that of the parent drug (SMZ); in cows 1 and 2 the plasma percentage of N4-SMZ versus SMZ in the elimination phase was 24.5% and 37%, respectively (Table 1). Protein binding (Table 2)
In calves 1 and 2 the plasma protein binding of N4-SMZ was higher than that of SMZ, in calf 3 they were equal and in the cows the protein binding of N4-SMZ was lower. In milk of both cows the protein binding of N4-SMZ and SMZ were 2.4% and 11.6%, respectively. Renal clearance (Table 3)
Both the renal clearance values of SMZ and its Nracetyl metabolite increased with age. In newborn calf no. 1 the renal clearance of N4-SMZ was 12.5 times faster than that of SMZ. Although in the other two calves and two cows the renal clearance rate of N4-SMZ itself was higher than in calf 1, it was relatively lower (only 4.1-5.4 times higher) than of SMZ compared with the 4-day-old calf. The urine pH of the animals was high (pH 7.2-8.9), resulting in a minimal passive tubular reabsorption of SMZ. 12
THE VETERINARY QUARTERLY. VOL, 13, No. 1, JANUARY 1991
100
10
PLASMA M I LK
SMZ
Cs
L_
Downloaded by [UAA/APU Consortium Library] at 12:00 16 October 2014
N,SMZ
0 U
0)0 2.4 h 0.1
0.01 1
20
10
0
30
Hours after injection
Figure 2.
Disposition of sulphamethoxazole (SMZ) and its N.racetyl metabolite (N4-SMZ) in plasma and milk of a dairy cow following intravenous administration of 10 mg SMZ/kg (11,2 = elimination half-life). DISCUSSION
Our pharmacokinetic data of SMZ in cows were in agreement with those found by Nielsen and Rasmussen (7). It is noteworthy that for the buffalo an elimination half-time that was three times longer (7 h) was reported (4). The percentage of SMZ and N4-SMZ binding to plasma proteins increased during the first two weeks after birth. The cause of this is the increase of albumen Table 2.
Plasma protein binding of sulphamethoxazole (SMZ) and its MI-acetyl metabolite (N4-SMZ).
Animal Calf 1 Calf 2 Calf 3 Cow I Cow 2
Age
Number of samples
4 days 7 days
6 6
14 days 3 years 4 years
6
6 6
Protein binding (e) SMZ
N4-SMZ
44.9±4.3 48.8±4.0 51.1±2.6 64.0±5.7 64.9±2.6
36.6±4.9* 43.1±3.6
52.6±1.6 52.9±4.6* 49.8±5.2*
Data are expressed as Mean ± SD. * Significantly different from that of SMZ (P
