High-performance liquid chromatography of sulphadimethoxine and its N1-glucuronide, N4-acetyl and N4-acetyl-N1-glucuronide metabolites in human plasma and urine

Kolmer

1992

Probenecid with its phase-I metabolites, and phase-II glucuronide conjugate can be analysed by a gradient high pressure liquid chromatographic method. Probenecid glucuronide in plasma with pH 7.4 is not stable and declines to 10% of the original value within 6 h (t1/2 approximately 1 h). Probenecid glucuronide is stable in urine with pH 5.0, moderately unstable at pH 6.0 (t1/2 approximately 10 h), and unstable at pH 8.0 (t1/2 approximately 0.5 h). Probenecid glucuronide is stable in water and 0.01 mol/l phosphoric acid in the autosampler of the high pressure liquid chromatograph. The decrease in concentration in water is 5.5% during 9 h and 0% in diluted acid. Probenecid glucuronide and the phase-I metabolites were not detectable in plasma. The main compound in fresh urine is the phase-II conjugate probenecid glucuronide (62% of a 500 mg dose); the phase-I metabolites are present and only a trace of probenecid is present. The percentage of the dose of the phase-I metabolites varies between 5 and 10, while hardly any probenecid is excreted unchanged (0.33%).

Section: Discussionsupporting

confidence: 85%

Direct measurement of probenecid and its glucuronide conjugate by means of high pressure liquid chromatography in plasma and urine of humans

Kolmer

1992

“…Known (measured after deconjugation) concentrations of the glucuronides in urine (25 ~1) were added to plasma (1 ml) [6][7][8]. Calibration curves for racemic oxazepam and temazepam were constructed by spiking plasma with known concentrations of the compounds (r = 0.999).…”

Section: Calibration Curve Of Plasma Glucuronidesmentioning

confidence: 99%

Direct high pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates

Baars²,

Wuis³

1991

Three high pressure liquid chromatographic systems for the separation of oxazepam, temazepam and their glucuronides (system A), the separation of their R,S glucuronide diastereomers (system B) and the chiral separation of the parent drugs (system C) are described. Preliminary pharmacokinetics of R,S-oxazepam and R,S-temazepam in a human volunteer reveal that the protein binding of the glucuronides is lower than that of the parent drugs, but that there is no difference in protein binding between the R-oxazepam/temazepam and S-oxazepam/temazepam and their corresponding glucuronides. The S-glucuronide is the main metabolite formed and excreted by man. The plasma ratio R/S-glucuronide is 1:1 for both oxazepam and temazepam. The renal clearance of R-temazepam, and S-temazepam are similar, and those of R-oxazepam and S-oxazepam tend to be different.

“…A similar procedure was followed for the measurement of N4-acetylsulfadimethoxine-N1-glucuronide [24].…”

Section: Concentrationmentioning

confidence: 99%

Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man

Kolmer

1990

Self Cite

Sulfadimethoxine is metabolized by O-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8 +/- 4.2 h versus 36.3 +/- 5.4 h; P = 0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3 +/- 5.2 h versus 53.5 +/- 8.5 h, P = 0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50-60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40-50% for excretion into bile and faeces.