PHARMACOKINETICS AND DISPOSITION Kyoung-Ah Kim Æ Sae Ock Oh Æ Pil-Whan Park Ji-Young Park Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects Received: 6 February 2005 / Accepted: 1 April 2005 / Published online: 25 May 2005 Ó Springer-Verlag 2005 Abstract Objectives: Carbamazepine (CBZ) undergoes biotransformation by CYP3A4 and CYP2C8, and glu- curonide conjugation. There has been no clear demon- stration to reveal the role of glucuronidation in the disposition of CBZ. We evaluated the effect of proben- ecid, a UDP-glucuronosyltransferase inhibitor, on the pharmacokinetics of CBZ in humans. Methods: In a randomized, open-label, two-way cross- over 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 lmol h/l to 1020.7 lmol h/l (P<0.001) while increasing that of CBZ-E from 137.6 lmol h/l to 183.5 lmol 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 ef- fect on the glucuronidation of CBZ and CBZ-E, it in- creased 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. Keywords Carbamazepine Æ Probenecid Æ Drug interaction Æ Cytochrome P 450 3A4 (CYP3A4) Æ UDP-glucurunosyl transferase Introduction Carbamazepine (CBZ) is one of the most commonly prescribed drugs for the prevention of partial seizure as well as for the treatment of generalized tonic–clonic seizures and trigeminal neuralgia [1]. CBZ has also been used to treat various psychiatric disorders, including acute mania, bipolar disorder, and borderline personal- ity disorder [2, 3]. Furthermore, CBZ has been reported to be useful in the augmentation of antidepressant drug responses in treatment-resistant depression [4]. CBZ undergoes hepatic biotransformation almost completely, with less than 5% of the dose excreted un- changed [5]. CBZ 10,11-epoxide (CBZ-E) is the principal active metabolite of CBZ, and this biotransformation is principally mediated by CYP3A4 and CYP2C8, with the former playing the most important role [6]. Subsequent hydration of CBZ-E to trans-10,11-dihydrodiol-carba- mazepine (CBZ-10,11-diol) is catalyzed by microsomal epoxide hydrolase [7]. Moreover, glucuronide conjuga- tion of CBZ is involved in CBZ biotransformation in humans [7–9]. The most important interactions affecting the disposition of CBZ are those resulting in the induction or inhibition of its metabolism. Clinically, a variety of drug interactions between CBZ and co- administered drugs have been reported. The actions of most drugs that affect CYP3A4 by inhibition or induc- K.-A. Kim Æ J.-Y. Park (&) Department of Pharmacology and Gil Medical Center, Gachon Medical School and Clinical Trial Center, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Korea E-mail: jypark@gachon.ac.kr Tel.: +82-32-4602151 Fax: +82-32-4225105 S. O. Oh Department of Anatomy, Pusan National University College of Medicine, Busan, Korea P.-W. Park Department of Laboratory medicine, Gil Medical Center, Gachon Medical School and Clinical Trial Center, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Korea Eur J Clin Pharmacol (2005) 61: 275–280 DOI 10.1007/s00228-005-0940-7