Vol. 27, No. 6 Printed in U.S.A.
PRESYSTEMIC METABOLISM OF ALBENDAZOLE: EXPERIMENTAL EVIDENCE OF AN EFFLUX PROCESS OF ALBENDAZOLE SULFOXIDE TO INTESTINAL LUMEN
´ ´ P. A. REDONDO, A. I. ALVAREZ, J. L. GARCIA, O. M. LARRODE, G. MERINO,AND
J. G. PRIETO
Laboratory of Animal Physiology, Faculty of Veterinary, University of Leon, Leon, Spain ´ ´ (Received April 2, 1998; accepted March 1, 1999)
This paper is available online at http://www.dmd.org
ABSTRACT: Albendazole (ABZ) presystemic clearance was studied in rat by perfusion of a 25 M ABZ solution in isolated intestinal loops. Significant secretion of the activemetabolite, ABZSO, into the lumen was observed. The metabolite was also present in mesenteric blood. After 30 min of intestinal perfusion, 64% of the ABZ dose had disappeared from lumen. The total amount of ABZSO measured was 0.341 0.04 nmol/cm with 0.176 0.03 nmol/cm in mesenteric blood. The metabolite secretion to intestinal lumen was 0.165 0.05 nmol/cm. Intestinal sulfoxidation was induced by repeatedadministration of ABZ and ABZ coadministered with surfactants, especially polysorbate 80. The enantioselectivity of the in vitro intestinal sulfoxidation of ABZ showed that the relative contribution of P-450 and flavin-containing monooxygenase was quite similar, but after the induction by ABZ coadministered with polysorbate 80, the cytochrome P-450 system contribution was significantly increased.The appearance of ABZSO in mesenteric blood clearance was also increased under these conditions.
Albendazole [ABZ;1 methyl(5-proylthio)1H-benzimidazole-2yl] carbamate is one of the most important benzimidazole derivatives used against liver flukes, tapeworms, and lung and gastrointestinal roundworms. It is effective in the treatment of human hydatidosis (Gil-Grande et al., 1993) andmicrosporidial species, emerging agents as opportunistic pathogens in persons infected with the human immunodeficiency virus (HIV) (Kelly et al., 1996; Didier, 1997). After oral administration, ABZ is oxidized to a sulfoxide (ABZSO), which is in part further oxidized to a sulfone (ABZSO2); albendazole sulfoxide is the main metabolite in vivo. The formation of ABZSO is directly associated with two differentmicrosomal enzymatic systems, cytochrome P-450 and flavin-containing monooxygenase (FMO). Previous studies into liver and intestine microsomes of rat (Moroni et al., 1995; Villaverde et al., 1995) have shown that both systems are similarly involved. ABZSO has two antipodes, enantiomers ( ) and ( ), produced from the chiral thioether albendazole, which can be separated by HPLC; ( )ABZSO isassociated with the activity of FMO, whereas the P-450 system participates in the production of ( )ABZSO (Delatour et al., 1991). The low aqueous solubility of albendazole influences its absorption. Recently, we obtained results on the coadministration of ABZ with surfactants, which modify the pharmacokinetic profile of ABZSO, increasing the area under curve (AUC). When ABZ was administered to rats in aformulation that included surfactants sodium taurocholate at 5 and 10 mM and polysorbate 80 (P80) at 0.0022% (0.016 mM),
This work was supported by Comision Interministerial de Ciencia y Tecnologia (CICYT) (Spain) (FAR 91/0748 project). 1 Abbreviations used are: ABZ, albendazole; ABZSO, albendazole sulfoxide; ABZSO2, albendazole sulfone; e.e., enantiomeric excess. Send reprint requests to: Julio G.Prieto, Laboratory of Animal Physiology, Faculty of Veterinary, University of Leon, E24071, Leon, Spain. E-mail: dfijpf@ ´ ´ unileon.es
ABZSO mean residence time values showed longer-lasting levels, particularly for the 0.016 mM P80 treatment (Redondo et al., 1998). The liver has been considered a predominant organ of drug bioconversion. However, recent research has suggested a significant...