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

Vree, T. B.; Kolmer, E. W. J. Beneken

doi:10.1007/bf01962691

Cited by 18 publications

(16 citation statements)

References 35 publications

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“…It is possible that probenecid glucuronide, after having been formed in the liver and released into the blood stream for transportation to the kidhey, is hydrolyzed immediately into probenecid. Probenecid glucuronide added to human plasma is hydrolyzed with a tl/2 of 0.5 h [36]. In that case, it is very unlikely that probenecid glucuronide will be excreted in the urine, certainly not in the percentages we found.…”

Section: Drug Metabolism Takes Place Solely In the Liver And The Kidmentioning

confidence: 70%

“…The HPLC analysis is described elsewhere [36]. In brief the HPLC system consisted of a Spectra Physics SP 8775 autosampler, a Spectra Physics SP 8800 ternary HPLC pump, a Kratos Spectroflow 757 UV detector, and a Spectra Physics SP 4290 integrator.…”

Section: Drug Analysis Of Probenecid and Its Metabolitesmentioning

confidence: 99%

“…For the construction of the calibration curve of probenecid glucuronide, 100 #1 plasma or urine, 100 gl of ~-glucuronidase (50,000 U/ml type LII, lyophilized powder from limpets Patella vulgata; Sigma, St. Louis, USA), and 800 gl of potassium dihydrogen phosphate buffer, pH 3.8, were incubated at 37~ for 6 h [36].…”

Section: Sample Treatmentmentioning

confidence: 99%

“…If probenecid not only interferes with the tubular secretion of drugs, but also with the yield of glucuronidation or conjugation [2 21 35], the glucuronide of both probenecid and the drug investigated must be measured in plasma and urine to validate the effect of probenecid on the glucuronidation of some drugs. Hence, a direct high pressure liquid chromatographic (HPLC) method for the measurement of probenecid and its ester/acyl glucuronide was first developed [36].…”

Section: Introductionmentioning

confidence: 99%

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Capacity-limited renal glucuronidation of probenecid by humans

Vree¹,

Kolmer²,

Wuis³

1992

Pharmaceutisch Weekblad Scientific Edition

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Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

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Section: Drug Metabolism Takes Place Solely In the Liver And The Kidmentioning

confidence: 70%

Section: Drug Analysis Of Probenecid and Its Metabolitesmentioning

confidence: 99%

Section: Sample Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Capacity-limited renal glucuronidation of probenecid by humans

Vree¹,

Kolmer²,

Wuis³

1992

Pharmaceutisch Weekblad Scientific Edition

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“…Probenecid, its metabolites and probenecid acyl glucuronide were measured by direct HPLC analysis as described earlier [6]. Probenecid and metabolites were obtained from Merck Sharp & Dohme and probenecid acyl glucuronide was isolated from human urine [6].…”

Section: Discussionmentioning

confidence: 99%

Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid

1993

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The aim of this pilot study was to demonstrate the possible inhibitory effect of probenecid on the renal glucuronidation and on the renal clearance of nalidixic acid in a human volunteer. Under acidic urine conditions, hardly any nalidixic acid is excreted unchanged (0.2%). It is excreted as acyl glucuronide (53.4%), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide 30.9%, and 7-carboxynalidixic acid (4.2%). Under probenecid co-medication the renal glucuronidation of nalidixic acid is reduced from 53% to 16%; the renal clearance of both nalidixic acid and 7-hydroxymethylnalidixic acid are reduced (p < 0.001); the intrinsic t1/2 of the metabolite 7-hydroxymethylnalidixic acid increased from 0.48 h to 4.24 h. The amount of acyl glucuronidation of 7-hydroxymethylnalidixic acid was not altered. The in vitro protein binding of both acyl glucuronides was increased, while no effect on the unconjugated compounds was seen. Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide.

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Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

Vree

Biggelaar-Martea

Wissen

et al. 1993

Biopharm & Drug Disp

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The aim of this investigation was to assess the pharmacokinetics of naproxen in 10 human subjects after an oral dose of 500 mg using a direct HPLC analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. The mean t1/2 of naproxen in 9 subjects was 24.7 +/- 6.4 h (range 16 to 36 h). The t1/2 of 7.4 as found in subject number 10 must, therefore, be regarded as an extraordinary case (p < 0.0153). Naproxen acyl glucuronide accounts for 50.8 +/- 7.32 per cent of the dose, its isomerized conjugate isoglucuronide for 6.5 +/- 2.0 per cent, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4 per cent, and its isoglucuronide for 5.5 +/- 1.3 per cent (n = 10; 100 h collection period). Naproxen and O-desmethylnaproxen are excreted in negligible amounts (< 1 per cent). Even though urine pH of the subjects was kept acid (range pH 5.0-5.5) in order to stabilize the acyl glucuronides, isomerization takes place in blood when the acyl glucuronide is released from the liver for excretion by the kidney. Binding to plasma proteins was measured as 98 per cent and 100 per cent, respectively for the unconjugated compounds naproxen and O-desmethylnaproxen. Binding of the acyl glucuronides was less, being 92 per cent; for naproxen acyl glucuronide, 66 per cent for naproxen isoglucuronide, 72 per cent for O-desmethylnaproxen acyl glucuronide and 42 per cent for O-desmethylnaproxen isoglucuronide.

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

Cited by 18 publications

References 35 publications

Capacity-limited renal glucuronidation of probenecid by humans

Capacity-limited renal glucuronidation of probenecid by humans

Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid

Pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans

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