Salazosulfapyridine

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Ingrid Ljungstedtpahlman - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp i plasma kinetics and plasma metabolites in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Larsinge Olsson, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl] azo] benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.2l/kg and total clearance (CLtot) was 18ml/min × kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1 ?? 3 hours, for 14C, corresponding to 5ASA metabolites, between 3 ?? 10 hours and for 3H, corresponding to sulfapyridine metabolites, between4 ?? 12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentration(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight.There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp v pharmacokinetics of sasp after a single intravenous or oral administration in the dog
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine(Sulfasalazine, SASP) labelled with 14C in the carboxyl group and with 3H in the benzenesulfonyl ring was administered intravenously or orally to male and female beagle dogs with and without bile fistulas in order to study the pharmacokinetics. After intravenous administration a plasma elimination half life (t1/2β) for SASP was calculated to 14 min. The volume of distribution (Vdss) was found to be 0.47l/kg and the total clearance was about 35ml/min × kg. After oral administration of 50, 250 or 500mg/kg the time for maximal plasma concentration of SASP was 1 ?? 3 hours and the maximal concentration was 2.81±1.42μM after a dose of 50mg/kg and 15.08±3.04μM after 500mg/kg body weight.The bioavailability varied between 5.4 ?? 30% which is within the same range as reported from studies in man. The renal clearance was between 0.1 ?? 0.2l/min × kg.Metabolites of SASP were separated by HPLC and identified by mass spectrometry. 5-aminosalicylic acid (5ASA), sulfapyridine (SP) and its glucuronide were found in plasma and urine. 5ASA, N-acetylated 5ASA (Ac5ASA), SP and unmetabolized SASP were found in faeces.The cumulative biliary excretion of SASP after i.v. administration was as a mean 95% of the administered dose. Similar figures were obtained for the 14C and 3H radioactivity. Thus a quantitative excretion of the unchanged drug was found in the bile during 24 hours after administration and >90% was recovered during the first 2hours. No metabolites were found in the bile. After oral administration of SASP 18% of the administered dose was recovered as the unchanged drug in bile, 17% as 14C and 19% as 3H radioactivity within 48 hours. As after intravenous administration no metabolites were found in bile after the oral administration.The total recovery of excreted radioactivity after i.v. and oral administration was 69 ?? 96%. The tritium radioactivity representing the SP metabolites was mainly found in urine, while carbon-14 representing SASP and 5ASA metabolites was preferentially excreted in fae ces. This is in accordance with the higher absorption of SP and its metabolites, compared to 5ASA which is poorly absorbed and thus mainly eliminated via faeces together with a small amount of unchanged SASP.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp iii metabolism and biliary excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The metabolites formed from [3H, 14C]Salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.The cumulative excretion of [14C, 3H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for 14C and 3H respectively. The corresponding figures for male rats were 88.0±4.1% for 14C and 88.1±4.2% for 3H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of 14C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The 3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp ii tissue distribution and excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The tissue distribution has been studied in rats of both sexes by whole body autoradiogra phy and by dissection of organs after both a single oral and single intravenous administration of radiolabelled Salazosulfapyridine (sulfasalazine, SASP). The compound was labelled in two different positions : 14C in the carboxyl group in the salicylic acid part of the molecule and 3H in the sulfonamide part of the molecule making it possible to follow the metabolites after cleavage of the azobridge.The results of these investigations showed that following oral administration, the drug remained mainly in the gastro-intestinal tract. At about 8 hours a certain tissue distribution was noticed for both 14C and 3H. The distribution pattern was very different for the two labellings : the 14C radioactivity was at that time heterogeneously distributed to certain tissues as liver, bone marrow, intestinal mucosa, kidney, lung, connective tissues, ovary, salivary and harderian gland, while the 3H radioactivity was evenly distributed to all tissues including the central nervous system. The radioactivity was almost eliminated from the tissues within 24 hours.Also after i.v. injection high concentration of radioactivity was found in the gastrointestinal tract. Already 5 min after administration 25% of the dose was found in the duodenum and 30% in the liver, indicating an extensive biliary excretion. Beside the gastrointestinal tract the highest radioactive concentrations were found in the liver, connective tissues, lung, kidney, and blood. The radioactivity of 14C labelled SASP decreased more rapidly than that of the 3H. The distribution pattern was roughly the same when comparing males and female rats. In the fetal tissues the 3H radioactivity passed the placental barrier at 4 hours after the injection and was distributed evenly in the fetal tissues, while the 14C radioactivity was only found in the fetal intestines in small amounts.Trace amounts of excreted radioactivity was found in milk. The milk to plasma ratio for 14C was 0.13±0.01 20 min after intravenous administration.The total recovery of excreted radioactivity in male rats at different doses was 73 ?? 89% for 14C and 79 ?? 92% for 3H. 14C radioactivity was mainly found in the faeces while the 3H activ ity was found in about the same amount in faeces and in urine. Female rats had less faecal excretion than males. Only trace amounts of radioactivity were found in the expired air.

Birgitta Sjoquist - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp i plasma kinetics and plasma metabolites in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Larsinge Olsson, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl] azo] benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.2l/kg and total clearance (CLtot) was 18ml/min × kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1 ?? 3 hours, for 14C, corresponding to 5ASA metabolites, between 3 ?? 10 hours and for 3H, corresponding to sulfapyridine metabolites, between4 ?? 12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentration(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight.There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp v pharmacokinetics of sasp after a single intravenous or oral administration in the dog
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine(Sulfasalazine, SASP) labelled with 14C in the carboxyl group and with 3H in the benzenesulfonyl ring was administered intravenously or orally to male and female beagle dogs with and without bile fistulas in order to study the pharmacokinetics. After intravenous administration a plasma elimination half life (t1/2β) for SASP was calculated to 14 min. The volume of distribution (Vdss) was found to be 0.47l/kg and the total clearance was about 35ml/min × kg. After oral administration of 50, 250 or 500mg/kg the time for maximal plasma concentration of SASP was 1 ?? 3 hours and the maximal concentration was 2.81±1.42μM after a dose of 50mg/kg and 15.08±3.04μM after 500mg/kg body weight.The bioavailability varied between 5.4 ?? 30% which is within the same range as reported from studies in man. The renal clearance was between 0.1 ?? 0.2l/min × kg.Metabolites of SASP were separated by HPLC and identified by mass spectrometry. 5-aminosalicylic acid (5ASA), sulfapyridine (SP) and its glucuronide were found in plasma and urine. 5ASA, N-acetylated 5ASA (Ac5ASA), SP and unmetabolized SASP were found in faeces.The cumulative biliary excretion of SASP after i.v. administration was as a mean 95% of the administered dose. Similar figures were obtained for the 14C and 3H radioactivity. Thus a quantitative excretion of the unchanged drug was found in the bile during 24 hours after administration and >90% was recovered during the first 2hours. No metabolites were found in the bile. After oral administration of SASP 18% of the administered dose was recovered as the unchanged drug in bile, 17% as 14C and 19% as 3H radioactivity within 48 hours. As after intravenous administration no metabolites were found in bile after the oral administration.The total recovery of excreted radioactivity after i.v. and oral administration was 69 ?? 96%. The tritium radioactivity representing the SP metabolites was mainly found in urine, while carbon-14 representing SASP and 5ASA metabolites was preferentially excreted in fae ces. This is in accordance with the higher absorption of SP and its metabolites, compared to 5ASA which is poorly absorbed and thus mainly eliminated via faeces together with a small amount of unchanged SASP.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp iii metabolism and biliary excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The metabolites formed from [3H, 14C]Salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.The cumulative excretion of [14C, 3H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for 14C and 3H respectively. The corresponding figures for male rats were 88.0±4.1% for 14C and 88.1±4.2% for 3H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of 14C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The 3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp ii tissue distribution and excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The tissue distribution has been studied in rats of both sexes by whole body autoradiogra phy and by dissection of organs after both a single oral and single intravenous administration of radiolabelled Salazosulfapyridine (sulfasalazine, SASP). The compound was labelled in two different positions : 14C in the carboxyl group in the salicylic acid part of the molecule and 3H in the sulfonamide part of the molecule making it possible to follow the metabolites after cleavage of the azobridge.The results of these investigations showed that following oral administration, the drug remained mainly in the gastro-intestinal tract. At about 8 hours a certain tissue distribution was noticed for both 14C and 3H. The distribution pattern was very different for the two labellings : the 14C radioactivity was at that time heterogeneously distributed to certain tissues as liver, bone marrow, intestinal mucosa, kidney, lung, connective tissues, ovary, salivary and harderian gland, while the 3H radioactivity was evenly distributed to all tissues including the central nervous system. The radioactivity was almost eliminated from the tissues within 24 hours.Also after i.v. injection high concentration of radioactivity was found in the gastrointestinal tract. Already 5 min after administration 25% of the dose was found in the duodenum and 30% in the liver, indicating an extensive biliary excretion. Beside the gastrointestinal tract the highest radioactive concentrations were found in the liver, connective tissues, lung, kidney, and blood. The radioactivity of 14C labelled SASP decreased more rapidly than that of the 3H. The distribution pattern was roughly the same when comparing males and female rats. In the fetal tissues the 3H radioactivity passed the placental barrier at 4 hours after the injection and was distributed evenly in the fetal tissues, while the 14C radioactivity was only found in the fetal intestines in small amounts.Trace amounts of excreted radioactivity was found in milk. The milk to plasma ratio for 14C was 0.13±0.01 20 min after intravenous administration.The total recovery of excreted radioactivity in male rats at different doses was 73 ?? 89% for 14C and 79 ?? 92% for 3H. 14C radioactivity was mainly found in the faeces while the 3H activ ity was found in about the same amount in faeces and in urine. Female rats had less faecal excretion than males. Only trace amounts of radioactivity were found in the expired air.

Nilsotto Ahnfelt - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp i plasma kinetics and plasma metabolites in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Larsinge Olsson, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl] azo] benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.2l/kg and total clearance (CLtot) was 18ml/min × kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1 ?? 3 hours, for 14C, corresponding to 5ASA metabolites, between 3 ?? 10 hours and for 3H, corresponding to sulfapyridine metabolites, between4 ?? 12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentration(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight.There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp v pharmacokinetics of sasp after a single intravenous or oral administration in the dog
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine(Sulfasalazine, SASP) labelled with 14C in the carboxyl group and with 3H in the benzenesulfonyl ring was administered intravenously or orally to male and female beagle dogs with and without bile fistulas in order to study the pharmacokinetics. After intravenous administration a plasma elimination half life (t1/2β) for SASP was calculated to 14 min. The volume of distribution (Vdss) was found to be 0.47l/kg and the total clearance was about 35ml/min × kg. After oral administration of 50, 250 or 500mg/kg the time for maximal plasma concentration of SASP was 1 ?? 3 hours and the maximal concentration was 2.81±1.42μM after a dose of 50mg/kg and 15.08±3.04μM after 500mg/kg body weight.The bioavailability varied between 5.4 ?? 30% which is within the same range as reported from studies in man. The renal clearance was between 0.1 ?? 0.2l/min × kg.Metabolites of SASP were separated by HPLC and identified by mass spectrometry. 5-aminosalicylic acid (5ASA), sulfapyridine (SP) and its glucuronide were found in plasma and urine. 5ASA, N-acetylated 5ASA (Ac5ASA), SP and unmetabolized SASP were found in faeces.The cumulative biliary excretion of SASP after i.v. administration was as a mean 95% of the administered dose. Similar figures were obtained for the 14C and 3H radioactivity. Thus a quantitative excretion of the unchanged drug was found in the bile during 24 hours after administration and >90% was recovered during the first 2hours. No metabolites were found in the bile. After oral administration of SASP 18% of the administered dose was recovered as the unchanged drug in bile, 17% as 14C and 19% as 3H radioactivity within 48 hours. As after intravenous administration no metabolites were found in bile after the oral administration.The total recovery of excreted radioactivity after i.v. and oral administration was 69 ?? 96%. The tritium radioactivity representing the SP metabolites was mainly found in urine, while carbon-14 representing SASP and 5ASA metabolites was preferentially excreted in fae ces. This is in accordance with the higher absorption of SP and its metabolites, compared to 5ASA which is poorly absorbed and thus mainly eliminated via faeces together with a small amount of unchanged SASP.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp iii metabolism and biliary excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The metabolites formed from [3H, 14C]Salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.The cumulative excretion of [14C, 3H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for 14C and 3H respectively. The corresponding figures for male rats were 88.0±4.1% for 14C and 88.1±4.2% for 3H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of 14C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The 3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp ii tissue distribution and excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The tissue distribution has been studied in rats of both sexes by whole body autoradiogra phy and by dissection of organs after both a single oral and single intravenous administration of radiolabelled Salazosulfapyridine (sulfasalazine, SASP). The compound was labelled in two different positions : 14C in the carboxyl group in the salicylic acid part of the molecule and 3H in the sulfonamide part of the molecule making it possible to follow the metabolites after cleavage of the azobridge.The results of these investigations showed that following oral administration, the drug remained mainly in the gastro-intestinal tract. At about 8 hours a certain tissue distribution was noticed for both 14C and 3H. The distribution pattern was very different for the two labellings : the 14C radioactivity was at that time heterogeneously distributed to certain tissues as liver, bone marrow, intestinal mucosa, kidney, lung, connective tissues, ovary, salivary and harderian gland, while the 3H radioactivity was evenly distributed to all tissues including the central nervous system. The radioactivity was almost eliminated from the tissues within 24 hours.Also after i.v. injection high concentration of radioactivity was found in the gastrointestinal tract. Already 5 min after administration 25% of the dose was found in the duodenum and 30% in the liver, indicating an extensive biliary excretion. Beside the gastrointestinal tract the highest radioactive concentrations were found in the liver, connective tissues, lung, kidney, and blood. The radioactivity of 14C labelled SASP decreased more rapidly than that of the 3H. The distribution pattern was roughly the same when comparing males and female rats. In the fetal tissues the 3H radioactivity passed the placental barrier at 4 hours after the injection and was distributed evenly in the fetal tissues, while the 14C radioactivity was only found in the fetal intestines in small amounts.Trace amounts of excreted radioactivity was found in milk. The milk to plasma ratio for 14C was 0.13±0.01 20 min after intravenous administration.The total recovery of excreted radioactivity in male rats at different doses was 73 ?? 89% for 14C and 79 ?? 92% for 3H. 14C radioactivity was mainly found in the faeces while the 3H activ ity was found in about the same amount in faeces and in urine. Female rats had less faecal excretion than males. Only trace amounts of radioactivity were found in the expired air.

Stig Andersson - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp i plasma kinetics and plasma metabolites in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Larsinge Olsson, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl] azo] benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.2l/kg and total clearance (CLtot) was 18ml/min × kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1 ?? 3 hours, for 14C, corresponding to 5ASA metabolites, between 3 ?? 10 hours and for 3H, corresponding to sulfapyridine metabolites, between4 ?? 12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentration(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight.There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp v pharmacokinetics of sasp after a single intravenous or oral administration in the dog
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine(Sulfasalazine, SASP) labelled with 14C in the carboxyl group and with 3H in the benzenesulfonyl ring was administered intravenously or orally to male and female beagle dogs with and without bile fistulas in order to study the pharmacokinetics. After intravenous administration a plasma elimination half life (t1/2β) for SASP was calculated to 14 min. The volume of distribution (Vdss) was found to be 0.47l/kg and the total clearance was about 35ml/min × kg. After oral administration of 50, 250 or 500mg/kg the time for maximal plasma concentration of SASP was 1 ?? 3 hours and the maximal concentration was 2.81±1.42μM after a dose of 50mg/kg and 15.08±3.04μM after 500mg/kg body weight.The bioavailability varied between 5.4 ?? 30% which is within the same range as reported from studies in man. The renal clearance was between 0.1 ?? 0.2l/min × kg.Metabolites of SASP were separated by HPLC and identified by mass spectrometry. 5-aminosalicylic acid (5ASA), sulfapyridine (SP) and its glucuronide were found in plasma and urine. 5ASA, N-acetylated 5ASA (Ac5ASA), SP and unmetabolized SASP were found in faeces.The cumulative biliary excretion of SASP after i.v. administration was as a mean 95% of the administered dose. Similar figures were obtained for the 14C and 3H radioactivity. Thus a quantitative excretion of the unchanged drug was found in the bile during 24 hours after administration and >90% was recovered during the first 2hours. No metabolites were found in the bile. After oral administration of SASP 18% of the administered dose was recovered as the unchanged drug in bile, 17% as 14C and 19% as 3H radioactivity within 48 hours. As after intravenous administration no metabolites were found in bile after the oral administration.The total recovery of excreted radioactivity after i.v. and oral administration was 69 ?? 96%. The tritium radioactivity representing the SP metabolites was mainly found in urine, while carbon-14 representing SASP and 5ASA metabolites was preferentially excreted in fae ces. This is in accordance with the higher absorption of SP and its metabolites, compared to 5ASA which is poorly absorbed and thus mainly eliminated via faeces together with a small amount of unchanged SASP.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp iii metabolism and biliary excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The metabolites formed from [3H, 14C]Salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.The cumulative excretion of [14C, 3H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for 14C and 3H respectively. The corresponding figures for male rats were 88.0±4.1% for 14C and 88.1±4.2% for 3H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of 14C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The 3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp ii tissue distribution and excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The tissue distribution has been studied in rats of both sexes by whole body autoradiogra phy and by dissection of organs after both a single oral and single intravenous administration of radiolabelled Salazosulfapyridine (sulfasalazine, SASP). The compound was labelled in two different positions : 14C in the carboxyl group in the salicylic acid part of the molecule and 3H in the sulfonamide part of the molecule making it possible to follow the metabolites after cleavage of the azobridge.The results of these investigations showed that following oral administration, the drug remained mainly in the gastro-intestinal tract. At about 8 hours a certain tissue distribution was noticed for both 14C and 3H. The distribution pattern was very different for the two labellings : the 14C radioactivity was at that time heterogeneously distributed to certain tissues as liver, bone marrow, intestinal mucosa, kidney, lung, connective tissues, ovary, salivary and harderian gland, while the 3H radioactivity was evenly distributed to all tissues including the central nervous system. The radioactivity was almost eliminated from the tissues within 24 hours.Also after i.v. injection high concentration of radioactivity was found in the gastrointestinal tract. Already 5 min after administration 25% of the dose was found in the duodenum and 30% in the liver, indicating an extensive biliary excretion. Beside the gastrointestinal tract the highest radioactive concentrations were found in the liver, connective tissues, lung, kidney, and blood. The radioactivity of 14C labelled SASP decreased more rapidly than that of the 3H. The distribution pattern was roughly the same when comparing males and female rats. In the fetal tissues the 3H radioactivity passed the placental barrier at 4 hours after the injection and was distributed evenly in the fetal tissues, while the 14C radioactivity was only found in the fetal intestines in small amounts.Trace amounts of excreted radioactivity was found in milk. The milk to plasma ratio for 14C was 0.13±0.01 20 min after intravenous administration.The total recovery of excreted radioactivity in male rats at different doses was 73 ?? 89% for 14C and 79 ?? 92% for 3H. 14C radioactivity was mainly found in the faeces while the 3H activ ity was found in about the same amount in faeces and in urine. Female rats had less faecal excretion than males. Only trace amounts of radioactivity were found in the expired air.

Masanori Hatsuoka - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp i plasma kinetics and plasma metabolites in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Larsinge Olsson, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine (Sulfasalazine, SASP, 2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl] azo] benzoic acid) labelled with 14C in the carboxyl group and with 3H in chemically as well as metabolically stable positions in the benzenesulfonyl ring was administered either intravenously or orally to male and female rats in order to study the plasma pharmacokinetics of SASP and the plasma profiles of the metabolites. After intravenous administration SASP was eliminated rapidly from plasma with a half-life (t1/2) of 8min. The volume of distribution (Vdss) of SASP was 0.2l/kg and total clearance (CLtot) was 18ml/min × kg. After oral administration, SASP was present in plasma mainly during the first 4 hours. The time for maximal concentration (Tmax) varied for SASP between 1 ?? 3 hours, for 14C, corresponding to 5ASA metabolites, between 3 ?? 10 hours and for 3H, corresponding to sulfapyridine metabolites, between4 ?? 12 hours. The inter-individual variation was considerable. The bioavai lability of SASP was 9% and independent of the dose. The maximal concentration(Cmax) and area under the curve (AUC) increased proportionally with the dose. The absorption of SASP was not influenced by fasting overnight.There was a clear sex difference in the metabolism of SASP. The plasma concentration of sulfapyridine metabolites in female rats was twice that in male rats. No hydroxylated metabolites were found in female rat plasma, whereas in the male rats, the hydroxylated sulfapyridine metabolites were the major metabolites.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp v pharmacokinetics of sasp after a single intravenous or oral administration in the dog
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Gunnar Fjellner, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    Salazosulfapyridine(Sulfasalazine, SASP) labelled with 14C in the carboxyl group and with 3H in the benzenesulfonyl ring was administered intravenously or orally to male and female beagle dogs with and without bile fistulas in order to study the pharmacokinetics. After intravenous administration a plasma elimination half life (t1/2β) for SASP was calculated to 14 min. The volume of distribution (Vdss) was found to be 0.47l/kg and the total clearance was about 35ml/min × kg. After oral administration of 50, 250 or 500mg/kg the time for maximal plasma concentration of SASP was 1 ?? 3 hours and the maximal concentration was 2.81±1.42μM after a dose of 50mg/kg and 15.08±3.04μM after 500mg/kg body weight.The bioavailability varied between 5.4 ?? 30% which is within the same range as reported from studies in man. The renal clearance was between 0.1 ?? 0.2l/min × kg.Metabolites of SASP were separated by HPLC and identified by mass spectrometry. 5-aminosalicylic acid (5ASA), sulfapyridine (SP) and its glucuronide were found in plasma and urine. 5ASA, N-acetylated 5ASA (Ac5ASA), SP and unmetabolized SASP were found in faeces.The cumulative biliary excretion of SASP after i.v. administration was as a mean 95% of the administered dose. Similar figures were obtained for the 14C and 3H radioactivity. Thus a quantitative excretion of the unchanged drug was found in the bile during 24 hours after administration and >90% was recovered during the first 2hours. No metabolites were found in the bile. After oral administration of SASP 18% of the administered dose was recovered as the unchanged drug in bile, 17% as 14C and 19% as 3H radioactivity within 48 hours. As after intravenous administration no metabolites were found in bile after the oral administration.The total recovery of excreted radioactivity after i.v. and oral administration was 69 ?? 96%. The tritium radioactivity representing the SP metabolites was mainly found in urine, while carbon-14 representing SASP and 5ASA metabolites was preferentially excreted in fae ces. This is in accordance with the higher absorption of SP and its metabolites, compared to 5ASA which is poorly absorbed and thus mainly eliminated via faeces together with a small amount of unchanged SASP.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp iii metabolism and biliary excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The metabolites formed from [3H, 14C]Salazosulfapyridine (sulfasalazine, SASP), were investigated in urine, faeces, bile and ten different organs from rats after a single oral or intravenous dose. The metabolites were fractionated by liquid chromatography and conclusively identified by mass spectrometry. The metabolites identified in urine were 5-aminosalicylic acid(5ASA), 5-acetamidosalicylic acid(Ac5ASA), sulfapyridine(SP) and 5-hydroxy-sulfapyridine (SPOH) together with glucuronide, sulphate and/or acetyl conjugates of SPOH. The female rats formed no or very small amounts of hydroxylated and conjugated metabolites compared to male rats.The collected organs and their major metabolite content were as follows : stomach(SASP), duodenum (SASP and SP), ileum (SASP and SP), caecum(SP, SPOH and AcSPOH), colon (SP), lung (SP and SASP), liver (SP, AcSP and SASP), kidney (SP, AcSP and SASP), thyroid (SASP) and testis (SP and AcSP).The metabolites found in bile after an oral dose were SP, AcSP and glucuronide and sulphate conjugates of these as well as Ac5ASA and unchanged SASP. The bile from male rats contained higher concentrations of conjugated metabolites than bile from female rats. Only intact SASP was found after the i.v. dose.The cumulative excretion of [14C, 3H]SASP was studied in bile collected during 24 hours after p.o. or i.v. administration. The recovery of total radioactivity in bile from female rats after i.v. administration was 101.6±1.8%(mean±SEM)and 103.5±1.4% of administered dose for 14C and 3H respectively. The corresponding figures for male rats were 88.0±4.1% for 14C and 88.1±4.2% for 3H. The excretion of SASP in bile after i.v. administration was 99.8 % of the administered dose in female rats and 85.9% in the male rats. After an oral dose the biliary excretion of 14C radioactivity representing SASP and5ASA metabolites was low, 3.86±0.79% for females and 5.71±0.95% for male rats. The 3H excretion including SASP but consisting most of SP metabolites was significantly higher in the male rats, 38.3±3.7% compared to 10.5±2.1% in female rats. The reason for this sex differences was the formation of hydroxylated SP and further conjugation in male rats. The biliary excretion of SASP after oral administration was similar in both sexes 2.74±0.37% for female rats and 2.52±0.45% for male rats. Since the biliary excretion of the unchanged drug was < 3 % after p.o. administration enterohepatic cycling was not studied.In conclusion, SASP underwent azoreduction to form 5ASA and SP. Both these metabolites were acetylated. SP was also hydroxylated particularly in the male rats. The SPOH was conjugated both with sulfate and glucuronic acid.

  • pharmacokinetics of Salazosulfapyridine sulfasalazine sasp ii tissue distribution and excretion of sasp in the rat after a single intravenous or oral administration
    Drug Metabolism and Pharmacokinetics, 1991
    Co-Authors: Birgitta Sjoquist, Nilsotto Ahnfelt, Stig Andersson, Roland Dargy, Masanori Hatsuoka, Ingrid Ljungstedtpahlman
    Abstract:

    The tissue distribution has been studied in rats of both sexes by whole body autoradiogra phy and by dissection of organs after both a single oral and single intravenous administration of radiolabelled Salazosulfapyridine (sulfasalazine, SASP). The compound was labelled in two different positions : 14C in the carboxyl group in the salicylic acid part of the molecule and 3H in the sulfonamide part of the molecule making it possible to follow the metabolites after cleavage of the azobridge.The results of these investigations showed that following oral administration, the drug remained mainly in the gastro-intestinal tract. At about 8 hours a certain tissue distribution was noticed for both 14C and 3H. The distribution pattern was very different for the two labellings : the 14C radioactivity was at that time heterogeneously distributed to certain tissues as liver, bone marrow, intestinal mucosa, kidney, lung, connective tissues, ovary, salivary and harderian gland, while the 3H radioactivity was evenly distributed to all tissues including the central nervous system. The radioactivity was almost eliminated from the tissues within 24 hours.Also after i.v. injection high concentration of radioactivity was found in the gastrointestinal tract. Already 5 min after administration 25% of the dose was found in the duodenum and 30% in the liver, indicating an extensive biliary excretion. Beside the gastrointestinal tract the highest radioactive concentrations were found in the liver, connective tissues, lung, kidney, and blood. The radioactivity of 14C labelled SASP decreased more rapidly than that of the 3H. The distribution pattern was roughly the same when comparing males and female rats. In the fetal tissues the 3H radioactivity passed the placental barrier at 4 hours after the injection and was distributed evenly in the fetal tissues, while the 14C radioactivity was only found in the fetal intestines in small amounts.Trace amounts of excreted radioactivity was found in milk. The milk to plasma ratio for 14C was 0.13±0.01 20 min after intravenous administration.The total recovery of excreted radioactivity in male rats at different doses was 73 ?? 89% for 14C and 79 ?? 92% for 3H. 14C radioactivity was mainly found in the faeces while the 3H activ ity was found in about the same amount in faeces and in urine. Female rats had less faecal excretion than males. Only trace amounts of radioactivity were found in the expired air.

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