Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5‐hydroxy‐ and N<sub>4</sub>‐acetylmetabolites in man

Vree, T. B.; Tijhuis, M. W.; Termond, E. F. S.; Nouws, J. F. M.

doi:10.1002/bdd.2510070305

Cited by 13 publications

(11 citation statements)

References 11 publications

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“…The renal clearance of 5-OH-STZ is equal to or slightly higher than that of creatinine, indicating that 5-OH-STZ is excreted mainly by glomerular filtration and partly by active tubular secretion. The same excretion mechanism has been observed in man, as the 5-OH-STZ excretion could be partly inhibited by probenecid (Vree et al, 1986).…”

Section: Discussionsupporting

confidence: 72%

“…more vulnerable for hydroxylation. Also in man (Vree et al, 1986) and in turtles (Vree et al, 1987c), methylation at the 4 position of the SMZ oxazoyl group greatly increases the susceptibility to hydroxylation, but in man the elimination half-life also increases three-fold from 9 h for SMZ to 26 h for STZ. Differences in STZ hydroxylation in several species (Kinabo & Nielsen, 1986;Vree et al, 1986;1987b,c;Vree & Hekster, 1987) may be explained by the presence of different amounts and/or types of P-450 cytochrome isoenzymes for hydroxylation in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…The techniques employed for blood, milk and urine sampling, the handling of samples, the HPLC analysis, the deglucuronidation procedure and the protein binding determination were performed as previously described (Nouws et al, 1986a;1988b;Vree & Hekster, 1985;Vree et al, 1986).…”

Section: Sampling and Drug Analysismentioning

confidence: 99%

“…1); it has recently been introduced for veterinary use. In man, STZ is extremely well hydroxylated (70%), and acetylation accounts for only 15%, whereas for SMZ the acetylation pathway predominates (Vree et al, 1986;Vree & Hekster, 1987a). In goats, STZ was excreted mainly as the parent drug; the N4-acetyl and 5-hydroxy derivatives accounted, respectively, for only 19 and 18% (Kinabo & Nielsen, 1986).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Nouws¹,

Vree

Mevius³

et al. 1989

J Vet Pharmacol Ther

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The pharmacokinetic analysis of plasma concentration--time curves after a single i.v. dose of 20 mg/kg sulphatroxazole (STZ) to calves and cows revealed a small distribution volume of STZ (mean VD(area) = 0.22-0.26 l/kg) and an age dependent elimination (mean t1/2 6.6-18.8 h). In calves and cows, STZ was extensively metabolized into the N4-acetyl and 5-hydroxy derivatives. In the plasma of calves, the N4-acetyl metabolite (N4-STZ) was present in greater amounts than the hydroxy metabolite (5-OH-STZ), while in cows' plasma concentration of these two metabolites were similar. In the milk of dairy cows STZ concentrations paralleled those of the metabolites and were approximately 21 times lower than corresponding plasma concentrations. The mean plasma protein binding of STZ and its metabolites ranged from 36.4 to 82.5% of total concentration. The N4-STZ derivative was excreted by tubular secretion; the 5-OH-STZ and the parent compound, mainly by glomerular filtration. In calves the majority of STZ administered was excreted as N4-STZ (40-52%), while in cows the parent drug dominated the urinary excretion (36%).

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Sampling and Drug Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Nouws¹,

Vree

Mevius³

et al. 1989

J Vet Pharmacol Ther

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“…Among those secreted are primary, secondary, tertiary and quaternary amines (Rennick 1981a). It appears that all of these substances show a mutually competitive inhibition in secretion, but no cross-inhibition by Knoefel & Huang (1959); Knoefel et (1986); Vree et al (1983Vree et al ( . 1986aVree et al ( ) al.…”

Section: Specificitymentioning

confidence: 93%

Saturable Pharmacokinetics in the Renal Excretion of Drugs

Ginneken

Rüssel

1989

Clinical Pharmacokinetics

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The renal excretion of drugs is the result of different mechanisms: glomerular filtration, passive back diffusion, tubular secretion and tubular reabsorption. Of these mechanisms the last 2 are saturable, as they involve carrier transport. This also implies that both tubular secretion and tubular reabsorption are susceptible to competition between similar substrates for a common carrier site. Furthermore, transport via these mechanisms is energy-dependent, so-called active transport, able to concentrate a drug. Tubular secretion takes place in the proximal tubule of the nephron. Many organic compounds are actively secreted, but there are separate carrier systems for anions and cations. Anions appear to be transported actively over the basolateral membrane and by a less efficient non-active carrier-mediated process (facilitated diffusion) over the brush border membrane. As a result of these mechanisms, anions tend to accumulate in proximal tubular cells. For cations, however, the active transport step operates over the brush border membrane, whereas the uptake of the cation in the cell occurs via facilitated diffusion over the basolateral membrane. Active reabsorption is most prominent for many nutrients and endogenous substrates (amino acids, glucose, vitamins), but various exogenous compounds also have a certain affinity for the reabsorptive carrier systems. Uricosuric drugs, for instance, interfere with carrier-mediated reabsorption of urate. The occurrence of saturable excretion routes causes dose-dependent, non-linear pharmacokinetics. In clinical pharmacokinetics, tubular secretion can adequately be described with the use of a Michaelis-Menten equation. This implies that a compound undergoing tubular secretion exhibits a concentration-dependent renal clearance. At low plasma concentrations the clearance will be maximal, and for several drugs may be as high as the effective renal plasma flow. Increasing concentrations cause decreasing renal clearance, until eventually the secretion mechanism becomes fully saturated. Then the excretion of the drug in urine will depend primarily on its net rate of filtration. It is important to realise that the non-linear kinetics will be evident from the plasma kinetics only when the saturable pathway contributes to at least some 20% of the total body clearance. Interactions with other substrates, however, are likely to occur even when only a very small amount of drug is transported by the carrier system. Non-linear kinetics inevitably lead to disproportionate accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pharmacokinetics and acetylation of sulfa‐2‐monomethoxine in humans

Vree

Kolmer

Shimoda

et al. 1992

Biopharm & Drug Disp

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In humans sulfa-2-monomethoxine (S) is metabolized by N4-acetylation (39.9 +/- 8.0 per cent). After an oral dose, S is eliminated biphasically (t1/2, 5.2 +/- 1.6 h and 13.2 +/- 3.4 h) which is similar in both fast and slow acetylators. The metabolite N4-acetylsulfa-2-monomethoxine (N4) is eliminated monophasically (t1/2, 30.0 +/- 5.7 h). The intrinsic mean residence time (MRT) of N4 is 33.5 +/- 8.8 h. The mean total body clearance of S is 11.6 +/- 2.7 ml min-1, and the Vdss is 12.3 +/- 1.01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min-1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min-1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41.0 +/- 6.2 per cent) and as N4 acetyl conjugate (39.9 +/- 8.0 per cent).

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Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5‐hydroxy‐ and N₄‐acetylmetabolites in man

Cited by 13 publications

References 11 publications

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Saturable Pharmacokinetics in the Renal Excretion of Drugs

Pharmacokinetics and acetylation of sulfa‐2‐monomethoxine in humans

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Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5‐hydroxy‐ and N4‐acetylmetabolites in man

Cited by 13 publications

References 11 publications

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Pharmacokinetics, metabolism and renal clearance of sulphatroxazole in calves and cows

Saturable Pharmacokinetics in the Renal Excretion of Drugs

Pharmacokinetics and acetylation of sulfa‐2‐monomethoxine in humans

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Product

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Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5‐hydroxy‐ and N₄‐acetylmetabolites in man