Analysis of N4-trideuteroacetylsulphamerazine and its metabolites sulphamerazine and N4-acetylsulphamerazine in man by means of high-performance liquid chromatography and mass spectrometry

Vree, T. B.; Tijhuis, M. W.; Baakman, M.; Hekster, Chiel A.

doi:10.1002/bms.1200100303

Cited by 13 publications

(4 citation statements)

References 14 publications

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“…Similar results have been found with N-acetylprocainamide (NAPA) where only 2.8% of the administered NAPA-13C was metabolized by deacetylation (Stec et al, 1980). In contrast, the existence of a deacetylation-acetylation equilibrium in man has been demonstrated with a sulphonamide, N4-acetyl-sulphamerazine (Vree et al, 1983). The success in demonstrating such an equilibrium depends on the position of the equilibrium.…”

Section: Short Report 613supporting

confidence: 66%

“…Since acetylation is the major pathway for the elimination of 5-AS we investigated if an equilibrium exists between its acetylation and deacetylation to see whether reversible N-acetylation might contribute to the action of 5-AS. Such reversibility of acetylation has been observed with some sulphonamides (Schroder, 1973;Vree et al, 1981Vree et al, , 1983 and might also occur with other acetylated drugs.…”

Section: Introduction Methodsmentioning

confidence: 58%

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Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Meese¹,

Fischer²,

Klotz³

1984

Brit J Clinical Pharma

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In two healthy male subjects the disposition of deuterated N‐(2H3) acetyl‐5‐aminosalicylic acid (d3‐ac‐5‐AS) was investigated after a single rectal dose of 500 mg d3‐ac‐5‐AS. Urine and plasma were analysed by h.p.l.c. and gas chromatography mass‐spectrometry. Peak concentrations of around 0.5 microgram/ml occurred within 6 h and plasma concentrations declined thereafter with a half‐life (t1/2) of about 6 h which was confirmed by urinary excretion data. Renal clearance of d3‐ac‐5‐AS ranged between 200 and 300 ml/min and only 4.4‐ 11.2% of the dose could be recovered in the 48 h urine. Since no undeuterated ac‐5‐AS could be detected in any of the plasma and urine samples an irreversible acetylation of 5‐AS is assumed in man.

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Section: Short Report 613supporting

confidence: 66%

Section: Introduction Methodsmentioning

confidence: 58%

Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Meese¹,

Fischer²,

Klotz³

1984

Brit J Clinical Pharma

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“…Vree et al reported deacetylation of acetylsulphamerazine (13,15), acetylsulphapyridine (16) and acetylsulphamethoxazole (16) in humans. Nouws et al reported the same for acetylsulphadimidine in calves (5) and carp (6), and acetylsulphatroxazole in calves (8).…”

Section: Discussionmentioning

confidence: 99%

“…Althpugh many metabolic pathways have been identified for sulphonamides, and especially in ruminants hydroxylation is the main metabolic pathway (2,3,19), it is well recognized that the main elimination route is the acetylation followed by renal excretion through the active transport system in many species other than dogs (14). Shimoda et al de-Acetylated metabolites of sulphonamides are deacetylated to their parent compounds in many species, including pigs (7,11,12), calves (5), and humans (13,15,16). Since these animal species have an extensive acetylation capacity, deacetylation of acetylated metabolites of sulphonamides has been recognized to be a part of the acetylation-deacetylation equilibrium and therefore to be an important factor affecting sulphonamide pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Deacetylation as a determinant of sulphonamide pharmacokinetics in pigs

Shimoda

Okamoto

Sikazwe

et al. 1997

Veterinary Quarterly

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SUMMARY Sulphamonomethoxine (SMM), sulphadimidine (SDD), sulphadiazine (SDZ) and their N4-acetyl derivatives (AcSMM, AcSDD and AcSDZ) were intravenously injected into Goettingen miniature pigs and deacetylation was evaluated from plasma concentration-time curves, renal excretion, and rate constants obtained from pharmacokinetic analysis, using a non-linear least-squares method. Deacetylated metabolite was detected in both plasma and urine after intravenous injection of AcSMM, AcSDD and AcSDZ. The area under the curve (AUC) values for the deacetylated metabolite were significantly higher than those for acetyl derivatives after AcSMM and AcSDD administration, but significantly lower after AcSDZ. After AcSMM and AcSDD injection, the concentration ratio between deacetylated metabolite and acetyl derivative was almost constant in the terminal linear phase and similar to that seen after injection of sulphonamide. After AcSDZ injection, however, a constant ratio was not observed. These results indicate that deacetylation can have a significant effect on the pharmacokinetics of SMM and SDD, but not on those of SDZ in pigs. The rate constant for deacetylation was significantly higher than that for acetylation for SMM and SDD, but significantly lower for SDZ. It is, therefore, concluded that deacetylation may be a determinant of the pharmacokinetics of SMM and SDD in pigs. It was, however, not a determinant of SDZ pharmacokinetics because N4-acetylation is not the main elimination route in pigs.

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Pharmacokinetics, acetylation‐deacetylation, renal clearance, and protein binding of sulphamerazine, N₄‐acetylsulphamerazine, and N₄‐trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators

Vree

Hekster

Baakman

et al. 1983

Biopharm & Drug Disp

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Sulphamerazine shows a clear acetylator phenotype. The half-life of elimination of sulphamerazine is 12 h in 'fast' and 24 h in 'slow' acetylators. N,-Acetylsulphamerazine is eliminated biphasically, characterized by half-lives of 5 and 12 h in 'fast' and 5 and 24 h in 'slow' acetylators.Protein binding of sulphamerazine (86 per cent) and N,-acetylsulphamerazine (92 per cent) is independent of acetylator phenotype or the origin of the compound, whether it is present in the body as parent compound or metabolite. The renal clearance of sulphamerazine (20 ml min -I ) and N,-acetylsulphamerazine (300-500 ml min I ) is independent of the acetylator type and the origin of the compound.The existence of an acetylation-deacetylation equilibrium in the metabolism of sulphamerazine has been demonstrated with the test drug N,-trideuteroacetylsulphamerazine. which inhibits the renal excretion and clearance of N,-acetylsulphamerazine.

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Analysis of N4-trideuteroacetylsulphamerazine and its metabolites sulphamerazine and N4-acetylsulphamerazine in man by means of high-performance liquid chromatography and mass spectrometry

Cited by 13 publications

References 14 publications

Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Deacetylation as a determinant of sulphonamide pharmacokinetics in pigs

Pharmacokinetics, acetylation‐deacetylation, renal clearance, and protein binding of sulphamerazine, N₄‐acetylsulphamerazine, and N₄‐trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators

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Analysis of N4-trideuteroacetylsulphamerazine and its metabolites sulphamerazine and N4-acetylsulphamerazine in man by means of high-performance liquid chromatography and mass spectrometry

Cited by 13 publications

References 14 publications

Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Deacetylation as a determinant of sulphonamide pharmacokinetics in pigs

Pharmacokinetics, acetylation‐deacetylation, renal clearance, and protein binding of sulphamerazine, N4‐acetylsulphamerazine, and N4‐trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators

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Pharmacokinetics, acetylation‐deacetylation, renal clearance, and protein binding of sulphamerazine, N₄‐acetylsulphamerazine, and N₄‐trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators