Received 6 May 2002 Revised 20 January 2003 Copyright # 2003 John Wiley & Sons, Ltd. Accepted 21 January 2003 BIOPHARMACEUTICS & DRUG DISPOSITION Biopharm. Drug Dispos. 24: 199–204 (2003) Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdd.355 Time Dependent Pharmacokinetics of Albendazole in Human A. Mirfazaelian a , M. R. Rouini a, * and S. Dadashzadeh b a Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155/6451, Tehran, Iran b Department of Pharmaceutics, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. Box 14155/6153, Tehran, Iran ABSTRACT: The pharmacokinetics of the main metabolites of albendazole (albendazole sulph- oxide (ABZ-SO) and albendazole sulphone (ABZ-SO 2 )) were studied in 12 healthy human volunteers in a double blind design on the first and last days of oral administration of 800 mg albendazole daily for 15 days. No significant differences were observed in C max , T max and V d =F of ABZ-SO, whereas the AUC, AUMC and T 1=2 of this metabolite were significantly reduced and Cl=F was significantly increased in multiple dosing. There were also no significant differences in the C max , T max , V d =F and T 1=2 of ABZ-SO 2 , whereas the AUC and AUMC of this metabolite were significantly reduced and Cl=F was significantly increased in multiple dosing. These observations suggest time dependent pharmacokinetics of albendazole (observed for ABZ-SO and ABZ-SO 2 ), which was explained on the basis of the induction of enzymes involved in the metabolism of ABZ-SO (albendazole sulphoxide) to metabolites other than albendazole sulphone in multiple dosing. Copyright # 2003 John Wiley & Sons, Ltd. Key words: albendazole; albendazole sulphoxide; albendazole sulphone; time dependency; pharmacokinetics; metabolism Introduction Albendazole (ABZ) is a benzimidazole carbamate used as the drug of choice in the treatment of echinococcosis [1]. Few studies exist on the disposition, pharmacokinetics, and concentra- tion-effect relationship of ABZ and its metabo- lites in the human. After oral administration, it is quickly oxidized into its pharmacologically active metabolite albendazole sulphoxide (ABZ-SO) [2]. Further liver oxidative meta- bolism produces albendazole sulphone (ABZ- SO 2 ), which is thought to be anthelminitically inactive. The parent compound is undetectable in the serum after administration to man [3,4], rats [5], sheep [2], cattle [6] and other species. There are various controversial reports on induction or inhibition of microsomal enzyme function by ABZ or its metabolites [7–10], which may indicate nonlinearity in the pharmacokinetics of this drug. In rats, enhanced sulphonation of the sulphoxide metabolite has been observed after multiple dose treatment with the parent com- pound, which suggests autoinduction [9,10]. In human hepatoma cells ABZ-SO and ABZ-SO 2 induced CYP1A2 and UDP-GT, whereas the parent compound is claimed to inhibit the activity of these enzymes. Steiger et al. [8] observed that ABZ-SO concentration is decreased in the steady state compared with the first dose in hydatid patients treated with ABZ. They attributed this decrease to auto-induced metabo- * Correspondence to: Biopharmaceutics Laboratory, Division of Pharmacokinetics, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155/6451, Tehran. Iran. E-mail: rouini@sina.tums.ac.ir