Nitrosamine formation from interaction of isosorbide dinitrate and hydroxyzine HCl, a tertiary amine

Abstract

The interaction of two drugs—isosorbide dinitrate (ISDN) and hydroxyzine hydrochloride (HZ), a tertiary amine—was studied in vitro, under conditions simulating those found in the stomach, to determine if nitrosamines are formed. Gas chromatography-mass spectrometry was used to monitor the latter compounds. We found that, in the presence of sodium nitrite, HZ undergoes oxidative cleavage and nitrosation, forming three nitrosamine compounds, N-(4-chlorophenyl)benzyl]- N′-nitro-sopiperazine (A), N′-[2-(2′-hydroxyethoxy)ethyl]- N′-nitrosopiperazine (B), and N, N′-dinitrosopiperazine (C). However, when ISDN (0.8 g) and HZ (2.0 g) were incubated together for 1 hr, only N-[ α-(4-chlorophenyl)benzyl]- N′-nitrosopiperazine (A) was recovered. Although preparations of HZ contain (A) as an impurity, the quantity is trivial (0.5 ng/mg drug), and the bulk of the material detected is formed by interaction of ISDN with HZ. Because some individuals may ingest isosorbide dinitrate and hydroxyzine HCl, or analogous combinations, over a period of years, the risk posed by this type of drug interaction should be determined.