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Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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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Authors and Affiliations

  1. Department of Pharmacology and Gil Medical Center, Gachon Medical School and Clinical Trial Center, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Korea

    Kyoung-Ah Kim & Ji-Young Park

  2. Department of Anatomy, Pusan National University College of Medicine, Busan, Korea

    Sae Ock Oh

  3. Department of Laboratory medicine, Gil Medical Center, Gachon Medical School and Clinical Trial Center, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Korea

    Pil-Whan Park

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  1. Kyoung-Ah Kim
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  2. Sae Ock Oh
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  4. Ji-Young Park
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Correspondence to Ji-Young Park.

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Kim, KA., Oh, S.O., Park, PW. et al. Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects. Eur J Clin Pharmacol 61, 275–280 (2005). https://doi.org/10.1007/s00228-005-0940-7

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  • DOI: https://doi.org/10.1007/s00228-005-0940-7

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