Pharmacokinetic properties of N‐nitrosofenfluramine after its administration to rats

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 ranginng from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation. Copyright © 2010 John Wiley & Sons, Ltd.