title: Pharmacokinetic properties of N-nitrosofenfluramine after its administration to rats.
abstract: N-nitrosofenfluramine (N-Fen), a synthetic adulterant in Chinese herbal diet products, is believed to cause hepatotoxicity in people who use these products. N-Fen is a relatively new compound, and thus pharmacological and toxicological studies are insufficient. The aim of this work was to (1) define N-Fen's plasma pharmacokinetics and tissue distribution after single intraperitoneal (i.p.) administration of 25 mg/kg to rats; (2) define its bioavailability; and (3) identify fenfluramine (Fen) and norfenfluramine (Norf) as N-Fen metabolites. N-Fen rapidly appeared in the circulation and was distributed to all tissues. Norf was found to be the primary metabolite and not Fen. Plasma and tissue levels of N-Fen and Norf were low with bioavailability of N-Fen after i.p. administration was <3%. The AUC(0) (-t) of N-Fen in the liver and kidney were 6.6 and 12.1 times, respectively, greater than the brain, and 17.8 and 32.6 times, respectively, greater than the plasma. In conclusion, N-Fen did not show local accumulation in the liver, the site of toxicity, with concentrations represented as percentage of the total dose ranging from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation.
authors.affiliation: Department of Clinical Pharmacy, Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Japan.
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Wada
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D005277:Fenfluramine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009642:Norfenfluramine; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D014018:Tissue Distribution
chemical_list: C493137:nitrosofenfluramine; D009642:Norfenfluramine; D005277:Fenfluramine