TOXICOLOGY AND APPLIED PHARMACOLOGY 92, 141-149 (1988) inducing Effect of Albendazole on Rat Liver Drug-Metabolizing Enzymes and Metabolite Pharmacokinetics HAJAR SOUHAILI-EL AMRI,* XAVIER FARGETTON,~ ETIENNE BENOIT,~ MURIEL TOTIS,* AND ANNE-MARIE BATT* With the Technical Collaboration of Christine Masson *Centre du Midicament, U.A. 597, Faculte’des Sciences Pharmaceutiques, 30 Rue Lionnois, F-54000 Nancy, and TLaboratoire de Biochimie, INRA 54189. Ecole Nationale Vethrinaire de Len, F-69752 Charbonnieres Cidex, France Received November 19, 1986; accepted August 4, 1987 Inducing Effect of Albendazole on Rat Liver Drug-Metabolizing Enzymes and Metabolite Pharmacokinetics. SOUHAILI-EL AMRI, H., FARGETTON, X., BENOIT, E., TOTIS, M., AND BAIT, A. M. (1988). Toxicol. Appl. Pharmacol. 92, 141-149. Albendazole (ABZ), methyl (5- (propylthio)- 1 H-benzimidazol-2-yl)carbamate, is a broad spectrum anthelmintic drug. S-oxida- tion to the sulfoxide (SO-ABZ) and the sulfone (SO*-ABZ) are the first steps ofits bioconversion. SO-ABZ is pharmacologically active and embryotoxic in rats. In the present study, rat liver microsomal drug-metabolizing enzymes were assayed after 10 days oral administration with 40 PmoI ABZ/kg per day. The activities of 4-nitroanisole O-demethylase, benzo[a]pyrene hydroxy- lase, ‘I-ethoxycoumarin 0-deethylase, and 7-ethoxyresorufin 0-deethylase increased 6, 7-, 8-, and 30-fold, respectively. By immunoblotting an increase in cytochrome P-448 was observed. UDP-glucuronosyltransferase (GT) type 1 activities (1-naphthol, 7-hydroxycoumarin, 4-nitro- phenol, and 4-methylumbelliferone) were significantly higher than in control microsomes (3- to 4-fold), while GT type 2 activities and bilirubin-GT remained unchanged. Microsomal epoxide hydrolase (benzo[a]pyrene oxide) increased 2-fold. Microsomal y-glutamyltransferase activity was unchanged. The in vivo SO-ABZ plasma level was decreased when the SO,-ABZ plasma level was increased. In vitro sulfoxidation and sulfonation were, however, unchanged. Although a range of imidazole derivatives, including benzimidazole itself, were commonly reported as inhibitors of monooxygenase activities, ABZ behaved as an inducer of cytochrome P-448, GT 1, and epoxide hydrolase. o 1988 Academic press, I~C. Albendazole (ABZ), methyl (5(propylthio)- the plasma of man (Penicaut et al., 1983; 1H-benzimidazol-2-yl)carbamate (Zentel, Maniner et al., 1986), rats (Delatour et al., Valbazen), is a broad-spectrum anthelmintic, 1984) cattle (Prichard et al., 1985), and widely used in human and veterinary medi- sheep (Marriner and Bogan, 1980) the parent cine (Saimot et al., 1983; Theodorides et al., compound remains undetectable (co.0 1 pg/ 1976). S-oxidations of the drug to albenda- ml). SO-ABZ is pharmacologically active and zole sulfoxide (SO-ABZ) and albendazole sul- embryotoxic in rats in contrast with SO*- fone (SO*-ABZ) are the first steps of biocon- ABZ, which is neither active nor toxic (Dela- version (Gyurik et al., 198 1). These oxida- tour et al., 198 1). Previous studies have dem- tions are of a primary importance in the onstrated that ABZ was converted to SO- expression of anthelmintic activity and toxic- ABZ and SO,-ABZ by rat liver microsomes ity of ABZ, since it has been shown that in (Fargetton et al., 1986). 141 0041-008X/88 $3.00 Copy&t Q 1988 by Academic Press, Inc. All rights of reprcdwtion in any form reserved.