title: Carbendazim: disposition, cellular permeability, metabolite identification, and pharmacokinetic comparison with its nanoparticle.
abstract: The purpose of this study was to systematically evaluate the pharmacokinetic profiles of carbendazim, a novel anticancer drug. Carbendazim reached the highest concentrations in stomach and small intestine by 1 h after oral administration (500 mg/kg) to tumor-bearing nude mice. Four hours later, carbendazim in the large intestine reached maximum concentrations, probably because of pH-induced precipitation of the drug in the large intestine. The highest concentrations of carbendazim in well-perfused tissues, solid tumor, and blood ranged from 63 to 164 microg/g by 4 h. The percentage of carbendazim distributed to solid tumor by 4 h was higher than most well-perfused tissues. Carbendazim concentrations in blood were similar to, or somewhat lower than, those in tumor and other tissues. By 24 h post-dosing, carbendazim concentrations in tissues and blood declined to almost basal levels. The total percentage of administered carbendazim eliminated in urine was 25.7%, and in feces 16.6% within 24 h. Carbendazim exhibited fast permeation across Caco-2 and HT-29 carcinoma cell lines with corresponding permeability coefficients 7.74-8.06 x 10(-5) and 6.8-8.42 x 10(-5) (cm/s). The overall plasma protein binding of carbendazim (0.2-125 microg/mL) assessed by ultrafiltration ranged from 60 to 74%. Comparative pharmacokinetics was conducted in rats by high-pressure liquid chromatography to evaluate the relative bioavailability of carbendazim versus its nanoparticle formulation. Carbendazim and its nanoparticle reached T(max) at 2.01 and 1.57 h, respectively. The relative bioavailability of nanoparticle carbendazim versus regular carbendazim was 166%. High-pressure liquid chromatography analysis of the rat serum obtained at 20 h after oral dosing revealed a carbendazim metabolite, which was identified by mass spectroscopy analysis as 2-aminobenzimidazole, a hydrolyzed product of carbendazim. Incubation of carbendazim with human and rat liver microsomes produced a metabolite identified by mass spectrometry as 5(6)- or 4(7)-hydroxyl carbendazim. The comprehensive pharmacokinetic information is important to the current clinical investigation of carbendazim.
authors.affiliation: Institute for Drug Development, 14960 Omicron Drive, San Antonio, Texas 78245, USA. Jiale@mail.nih.gov
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Hong
authors.initials: H
authors.lastname: Wong
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Garza
authors.forename: Steve D
authors.initials: SD
authors.lastname: Weitman
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D018938:Caco-2 Cells / Q000378:metabolism; D002219:Carbamates; D002463:Cell Membrane Permeability / Q000502:physiology*; D019073:HT29 Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology / Q000379:methods*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D001562:Benzimidazoles; D002219:Carbamates; C006698:carbendazim