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Pharmaceutisch Weekblad

, Volume 14, Issue 5, pp 325–331 | Cite as

Capacity-limited renal glucuronidation of probenecid by humans

A pilotVmax-finding study
  • T. B. Vree
  • E. W. J. Van Ewijk-Beneken Kolmer
  • E. W. Wuis
  • Y. A. Hekster
Practice/Case Reports

Abstract

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet1/2 increased from 3 to 6 h. TheCmax was 14μg/ml with a dosage of 250 mg, 31μg/ml with 500 mg, 70μg/ml with 1,000 mg and 120μg/ml with 1,500 mg. Thetmax 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 glucuronidein 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 700μg/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 itsVmax of formation.

Keywords

Clearance, renal Glucuronates Metabolism Pharmacokinetics Probenecid 

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References

  1. 1.
    Beyer KH. New concept of competitive inhibition of the renal tubular excretion of penicillin. Science 1947;105:94–5.Google Scholar
  2. 2.
    Beyer KH. Functional characteristics of renal transport mechanisms. Pharmacol Rev 1950;2:227–80.Google Scholar
  3. 3.
    Beyer KH, Russo HF, Tillson EK, Miller AK, Verwey WF, Gass SR. Benemid,p-(di-n-propylsulfamyl)-benzoic acid: its renal affinity and its elimination. Am J Physiol 1951;166:625–40.PubMedGoogle Scholar
  4. 4.
    Beyer KH. Factors basic to the development of useful inhibitors of renal transport mechanisms. Arch Int Pharmacodyn Ther 1954;48:97–117.Google Scholar
  5. 5.
    Gutman AB, Yü TF. Renal function in gout, with a commentary on the renal regulation of urate excretion, and the role of the kidneys in the pathogenesis of gout. Am J Med 1957;23:600–25.PubMedGoogle Scholar
  6. 6.
    Weiner IM, Washington JA, Mudge GH. On the mechanism of action of probenecid on renal tubular secretion. Bull Johns Hopkins Hosp 1960;106:333–46.PubMedGoogle Scholar
  7. 7.
    Cunningham RF, Israeli ZH, Dayton PG. Clinical pharmacokinetics of probenecid. Clin Pharmacokinet 1981;135:135–51.Google Scholar
  8. 8.
    Dayton PG, Perel JM, Cunningham RF, Israeli ZH, Weiner IM. Studies of the fate of metabolites and analogs of probenecid. Drug Metab Dispos 1973;1:742–51.PubMedGoogle Scholar
  9. 9.
    Israeli ZH, Perel JM, Cunningham RF, Dayton PG, Yü TF, Gutman AB, et al. Metabolites of probenecid. Chemical, physical and pharmacological studies. J Med Chem 1972;15:709–13.PubMedGoogle Scholar
  10. 10.
    Dayton PG, Yü TF, Chen W, Berger L, West LA, Gutman AB. The physiological disposition of probenecid, including renal clearance, in man, studied by an improved method for its estimation in biological material. J Pharmacol Exp Ther 1963;140:278–85.PubMedGoogle Scholar
  11. 11.
    Ho JC, Conway WD, Melethil S. Probenecid disposition by parallel Michaelis-Menten and dose dependent pseudo first order processes. J Pharm Sci 1986;75:664–8.PubMedGoogle Scholar
  12. 12.
    Upton RA, Buskin JN, Williams RL, Holford NHG, Riegelman S. Negligible excretion of unchanged ketoprofen, naproxen and probenecid in urine. J Pharm Sci 1980;69:1254–7.PubMedGoogle Scholar
  13. 13.
    Eggers NJ, Doust K. Isolation and identification of probenecid acyl glucuronide. J Pharm Pharmacol 1981;33:123–4.PubMedGoogle Scholar
  14. 14.
    Dickinson RG, Hooper WD, Eadie MJ. pH dependent rearrangement of the biosynthetic ester glucuronide of valproic acid toβ-glucuronidase-resistant forms. Drug Metab Dispos 1984;12:247–52.PubMedGoogle Scholar
  15. 15.
    Faed EM. Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs. Drug Metab Rev 1984;15:1213–49.PubMedGoogle Scholar
  16. 16.
    Hansen-Møller J, Dalgaard L, Hansen SH. Reversed phase HPLC assay for the simultaneous determination of diflunisal and its glucuronides in serum and urine. Rearrangement of the 1-O-acylglucuronide. J Chromatogr Biomed Appl 1987;420:99–109.CrossRefGoogle Scholar
  17. 17.
    Hasegawa J, Smith PC, Benet LZ. Apparent intramolecular acyl migration of zomepirac glucuronide. Drug Metab Dispos 1982;10:469–73.PubMedGoogle Scholar
  18. 18.
    Illing HPA, Wilson ID. pH dependent formation ofβ-glucuronidase resistant conjugates from the biosynthetic ester glucuronide of isoxepac. Biochem Pharmacol 1981;30:3381–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Janssen FW, Kirkman SK, Fenselau C, Stogniew M, Hofmann BR, Young EM, et al. Metabolic formation of N- and O-glucuronides of 3-(p-chlorophenyl)thiazolo [3,2-a]benzimidazole-2-acetic acid. Rearrangement of the 1-O-acyl glucuronide. Drug Metab Dispos 1982;10:599–604.PubMedGoogle Scholar
  20. 20.
    Loewen GR, Macdonald JI, Verbeeck RK. High performance liquid chromatographic method for the simultaneous quantitation of diflunisal and its glucuronide and sulfate conjugates in human urine. J Pharm Sci 1989;78:250–5.PubMedGoogle Scholar
  21. 21.
    Schachter D. The chemical elimination of acyl glucuronides and its application to studies on the metabolism of benzoate and salicylate in man. J Clin Invest 1957;36:297–302.PubMedGoogle Scholar
  22. 22.
    Sinclair KA, Caldwell J. The formation ofβ-glucuronidase resistant glucuronides by the intramolar rearrangement of glucuronic acid conjugates at mild alkaline pH. Biochem Pharmacol 1982;31:953–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Smith PC, Hasegawa J, Langendijk PNJ, Benet LZ. Stability of acyl glucuronides in blood, plasma, and urine: studies with zomepirac. Drug Metab Dispos 1985;13:110–2.PubMedGoogle Scholar
  24. 24.
    Guarino AM, Schanker LS. Biliary excretion of probenecid and its glucuronide. J Pharmacol Exp Ther 1968;164:387–95.PubMedGoogle Scholar
  25. 25.
    Perel JM, Dayton PG, Yü TF, Gutman AB. Studies of the renal excretion of probenecid acyl glucuronidation in man. Eur J Clin Pharmacol 1971;3:106–12.CrossRefGoogle Scholar
  26. 26.
    Tillson EK, Schuchardt GS, Fishman JK, Beyer KH. The determination of probenecid (Benemid) in body fluids. J Pharmacol Exp Ther 1954;111:385–403.PubMedGoogle Scholar
  27. 27.
    Gisclon LG, Boyd RA, Williams RL, Giacomini KM. The effect of probenecid on the renal elimination of cimetidine. Clin Pharmacol Ther 1989;45:444–52.PubMedGoogle Scholar
  28. 28.
    Paxton JW. Interaction of probenecid with the protein binding of methotrexate. Pharmacology 1984;28:86–9.PubMedGoogle Scholar
  29. 29.
    Russel FGM, Wouterse AC, Van Ginneken CAM. Physiologically based pharmacokinetic model for the renal clearance of phenolsulfonphthalein and the interaction with probenecid and salicyluric acid in the dog. J Pharmacokinet Biopharm 1987;15:349–68.CrossRefPubMedGoogle Scholar
  30. 30.
    Smith PC, Langendijk PNJ, Bosso JA, Benet LZ. Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac. Clin Pharmacol Ther 1985;38:121–7.PubMedGoogle Scholar
  31. 31.
    Spahn H, Iwakawa S, Benet LZ, Lin ET. Influence of probenecid on the urinary excretion rates of the diastereomeric benoxaprofen glucuronides. Eur J Drug Metab Pharmacokinet 1987;12:233–7.PubMedGoogle Scholar
  32. 32.
    Spahn H, Spahn I, Benet LZ. Probenecid-induced changes in the clearance of carprofen enantiomers: a preliminary study. Clin Pharmacol Ther 1989;48:500–5.Google Scholar
  33. 33.
    Stoeckel K, Dubach UC, McNamara PJ. Effect of probenecid on the elimination and protein binding of ceftriaxone. Eur J Clin Pharmacol 1988;34:151–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Upton RA, Williams RL, Buskin JN, Jones RM. Effects of probenecid on ketoprofen kinetics. Clin Pharmacol Ther 1982;31:705–12.PubMedGoogle Scholar
  35. 35.
    Abernethey DR, Greenblatt DJ, Ameer B, Shader RI. Probenecid impairment of acetominophen and lorazepam clearance. Direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther 1985;38:121–7.Google Scholar
  36. 36.
    Vree TB, Beneken Kolmer EWJ. Direct measurement of probenecid and its glucuronide conjugate by means of high pressure liquid chromatography in plasma and urine of humans. Pharm Weekbl [Sci] 1992;14(3):83–7.Google Scholar
  37. 37.
    Anonymous. SAS user's guide. Basics 1982 edition. Cary: SAS Institute Inc., 1982.Google Scholar
  38. 38.
    Verwey-Van Wissen CPWGM, Koopman-Kimenai PM, Vree TB. Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electron capture detection. J Chromatogr Biomed Appl 1991;570:309–20.CrossRefGoogle Scholar
  39. 39.
    Vree TB, Baars AM, Wuis EW. Direct high-performance liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates. Pharm Weekbl [Sci] 1991;13:83–91.Google Scholar
  40. 40.
    Dayton PG, Cucinell SA, Weiss M, Perel JM. Dose-dependence of drug plasma level decline in dogs. J Pharmacol Exp Ther 1967;158:305–16.PubMedGoogle Scholar
  41. 41.
    Melethil S, Conway WD. Urinary excretion of probenecid and its metabolites in humans as a function of dose. J Pharm Sci 1976;65:861–5.PubMedGoogle Scholar
  42. 42.
    Guggino WB, Guggino SE. Renal anion transport. Kidney Int 1989;36:385–91.PubMedGoogle Scholar
  43. 43.
    Sperber I. Secretion of organic anions in the formation of urine and bile. Pharmacol Rev 1959;11:109–34.PubMedGoogle Scholar
  44. 44.
    Emanuelsson BM, Paalzow LK. Dose-dependent pharmacokinetics of probenecid in the rat. Biopharm Drug Dispos 1988;9:59–70.PubMedGoogle Scholar
  45. 45.
    Roos BE, Wickström G, Hartvig P, Nilsson JLG. Quantitation of CSF concentrations and biological activity of probenecid metabolites. Eur J Clin Pharmacol 1980;17:223–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Chiang CW, Benet LZ. Dose-dependent kinetics of probenecid in rhesus monkeys. Intravenous bolus studies. Pharmacology 1981;23:326–36.PubMedGoogle Scholar
  47. 47.
    Nouws JFM, Vree TB, Breukink HJ, Baakman M, Driessens F, Smulders A. Dose dependent disposition of sulphadimidine and of its N4-acetyl and hydroxy metabolites in plasma and milk of dairy cows. Vet Q 1985;7:177–86.PubMedGoogle Scholar
  48. 48.
    Selen A, Amidon GL, Welling PG. Pharmacokinetics of probenecid following oral doses to human volunteers. J Pharm Sci 1982;71:1238–42.PubMedGoogle Scholar
  49. 49.
    Gigon PL, Guarino AM. Uptake of probenecid by rat liver slices. Biochem Pharmacol 1970;19:2653–62.CrossRefPubMedGoogle Scholar
  50. 50.
    Vree TB, Beneken Kolmer EWJ, Martea M, Bosch R, Hekster YA, Shimoda M. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in humans. Pharm Weekbl [Sci] 1990;12:71–5.Google Scholar
  51. 51.
    Vree TB, Beneken Kolmer EWJ, Hekster YA, Shimoda M, Ono M, Miura T. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfa-6-monomethoxine in humans. Drug Metab Dispos 1990;18:852–8.PubMedGoogle Scholar
  52. 52.
    Vree TB, Beneken Kolmer EWJ, Hekster YA. Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfamethomidine in humans. Pharm Weekbl [Sci] 1991;13:198–206.Google Scholar
  53. 53.
    Vree TB, Beneken Kolmer EWJ, Hekster YA. High pressure liquid chromatographic analysis and preliminary pharmacokinetics of sulfaphenazole and its N2-glucuronide and N4-acyl metabolites in plasma and urine of man. Pharm Weekbl [Sci] 1990;12:243–7.Google Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • T. B. Vree
    • 1
  • E. W. J. Van Ewijk-Beneken Kolmer
    • 1
  • E. W. Wuis
    • 1
  • Y. A. Hekster
    • 1
  1. 1.Department of Clinical PharmacyUniversity Hospital NijmegenHB NijmegenThe Netherlands

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