Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects

Kyoung Ah Kim, Ock Oh Sae, Pil Whan Park, Ji-Young Park

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Objectives: Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glucuronide conjugation. There has been no clear demonstration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of probenecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. Methods: In a randomized, open-label, two-way crossover study, ten healthy male subjects were treated twice daily for 10 days with 500 mg probenecid or with a matched placebo. On day 6, a single dose of 200 mg CBZ was administered orally. Concentrations of CBZ and CBZ 10,11-epoxide (CBZ-E) in plasma and urine were measured. Results: Probenecid decreased the area under the plasma concentration-time curve (AUC) of CBZ from 1253.9 μmol h/l to 1020.7 μmol h/l (P<0.001) while increasing that of CBZ-E from 137.6 μmol h/l to 183.5 μmol h/l (P=0.033). The oral clearance of CBZ was increased by probenecid by 26% (90% confidence interval, 17-34%; P<0.001). Probenecid increased the AUC ratio of CBZ-E/CBZ from 0.11 to 0.16 (P<0.001). However, probenecid had minimal effect on the recovery of the conjugated and free forms of CBZ and CBZ-E in urine. Conclusion: Although probenecid showed a minimal effect on the glucuronidation of CBZ and CBZ-E, it increased CBZ biotransformation to CBZ-E, most likely reflecting the induction of CYP3A4 and CYP2C8 activities, in humans. These results demonstrate that glucuronide conjugation plays a minor role in the metabolism of CBZ and CBZ-E in humans, and that probenecid has an inducing effect on the disposition of CBZ.

Original languageEnglish
Pages (from-to)275-280
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume61
Issue number4
DOIs
Publication statusPublished - 2005 Jun 1
Externally publishedYes

Fingerprint

Probenecid
Carbamazepine
Healthy Volunteers
Pharmacokinetics
Cytochrome P-450 CYP3A
Glucuronides
Biotransformation
Area Under Curve
Urine
Glucuronosyltransferase

Keywords

  • Carbamazepine
  • Cytochrome P 3A4 (CYP3A4)
  • Drug interaction
  • Probenecid
  • UDP-glucurunosyl transferase

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects. / Kim, Kyoung Ah; Sae, Ock Oh; Park, Pil Whan; Park, Ji-Young.

In: European Journal of Clinical Pharmacology, Vol. 61, No. 4, 01.06.2005, p. 275-280.

Research output: Contribution to journalArticle

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abstract = "Objectives: Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glucuronide conjugation. There has been no clear demonstration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of probenecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. Methods: In a randomized, open-label, two-way crossover study, ten healthy male subjects were treated twice daily for 10 days with 500 mg probenecid or with a matched placebo. On day 6, a single dose of 200 mg CBZ was administered orally. Concentrations of CBZ and CBZ 10,11-epoxide (CBZ-E) in plasma and urine were measured. Results: Probenecid decreased the area under the plasma concentration-time curve (AUC) of CBZ from 1253.9 μmol h/l to 1020.7 μmol h/l (P<0.001) while increasing that of CBZ-E from 137.6 μmol h/l to 183.5 μmol h/l (P=0.033). The oral clearance of CBZ was increased by probenecid by 26{\%} (90{\%} confidence interval, 17-34{\%}; P<0.001). Probenecid increased the AUC ratio of CBZ-E/CBZ from 0.11 to 0.16 (P<0.001). However, probenecid had minimal effect on the recovery of the conjugated and free forms of CBZ and CBZ-E in urine. Conclusion: Although probenecid showed a minimal effect on the glucuronidation of CBZ and CBZ-E, it increased CBZ biotransformation to CBZ-E, most likely reflecting the induction of CYP3A4 and CYP2C8 activities, in humans. These results demonstrate that glucuronide conjugation plays a minor role in the metabolism of CBZ and CBZ-E in humans, and that probenecid has an inducing effect on the disposition of CBZ.",
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AU - Kim, Kyoung Ah

AU - Sae, Ock Oh

AU - Park, Pil Whan

AU - Park, Ji-Young

PY - 2005/6/1

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N2 - Objectives: Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glucuronide conjugation. There has been no clear demonstration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of probenecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. Methods: In a randomized, open-label, two-way crossover study, ten healthy male subjects were treated twice daily for 10 days with 500 mg probenecid or with a matched placebo. On day 6, a single dose of 200 mg CBZ was administered orally. Concentrations of CBZ and CBZ 10,11-epoxide (CBZ-E) in plasma and urine were measured. Results: Probenecid decreased the area under the plasma concentration-time curve (AUC) of CBZ from 1253.9 μmol h/l to 1020.7 μmol h/l (P<0.001) while increasing that of CBZ-E from 137.6 μmol h/l to 183.5 μmol h/l (P=0.033). The oral clearance of CBZ was increased by probenecid by 26% (90% confidence interval, 17-34%; P<0.001). Probenecid increased the AUC ratio of CBZ-E/CBZ from 0.11 to 0.16 (P<0.001). However, probenecid had minimal effect on the recovery of the conjugated and free forms of CBZ and CBZ-E in urine. Conclusion: Although probenecid showed a minimal effect on the glucuronidation of CBZ and CBZ-E, it increased CBZ biotransformation to CBZ-E, most likely reflecting the induction of CYP3A4 and CYP2C8 activities, in humans. These results demonstrate that glucuronide conjugation plays a minor role in the metabolism of CBZ and CBZ-E in humans, and that probenecid has an inducing effect on the disposition of CBZ.

AB - Objectives: Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glucuronide conjugation. There has been no clear demonstration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of probenecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. Methods: In a randomized, open-label, two-way crossover study, ten healthy male subjects were treated twice daily for 10 days with 500 mg probenecid or with a matched placebo. On day 6, a single dose of 200 mg CBZ was administered orally. Concentrations of CBZ and CBZ 10,11-epoxide (CBZ-E) in plasma and urine were measured. Results: Probenecid decreased the area under the plasma concentration-time curve (AUC) of CBZ from 1253.9 μmol h/l to 1020.7 μmol h/l (P<0.001) while increasing that of CBZ-E from 137.6 μmol h/l to 183.5 μmol h/l (P=0.033). The oral clearance of CBZ was increased by probenecid by 26% (90% confidence interval, 17-34%; P<0.001). Probenecid increased the AUC ratio of CBZ-E/CBZ from 0.11 to 0.16 (P<0.001). However, probenecid had minimal effect on the recovery of the conjugated and free forms of CBZ and CBZ-E in urine. Conclusion: Although probenecid showed a minimal effect on the glucuronidation of CBZ and CBZ-E, it increased CBZ biotransformation to CBZ-E, most likely reflecting the induction of CYP3A4 and CYP2C8 activities, in humans. These results demonstrate that glucuronide conjugation plays a minor role in the metabolism of CBZ and CBZ-E in humans, and that probenecid has an inducing effect on the disposition of CBZ.

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