N-nitrosylation potential of mono-N-desethylamiodarone at physiological pH.
Amiodarone (AMI) is frequently used for the treatment of supraventricular arrhythmias. The parent drug is rapidly dealkylated to mono-N-desethylamiodarone (MDEA) and the plasma concentrations of AMI and MDEA are comparable. MDEA is a secondary amine and may thus undergo formation to the corresponding N-nitrosamine in combination with coadministered nitrovasodilators. Previous studies have shown that nitrovasodilators release the vasoactive NO? which may nitrosylate thiol or secondary amine groups in aqueous solutions. Therefore, the nitrosylation potential of MDEA at physiological pH was investigated. N-Nitroso-monodesethylamiodarone (NO-MDEA) was synthesized, characterized and used as a reference product for the detection of the corresponding N-nitrosamine. HPLC and NMR results have shown that the NO-MDEA product is an equilibrium of two configurational isomers (syn and anti). NO-release was generated by sodium nitroprusside (SNP) which was exposed to light. The formation to NO-MDEA was assayed by HPLC-UV. It has been found that MDEA is nitrosylated in the higher nanomolar range and that varying oxygenation of the reaction mixture did not significantly affect the reaction yields. The addition of thiols such as serum albumin (0.6mM), l-cysteine (2.5mM) or N-acetylcysteine (2.5mM) inhibited the NO-MDEA formation indicating that they may prevent N-nitrosamine formation in vivo. However, as S-nitrosothiols may also release NO?, in long term exposure to elevated levels of nitric oxide the nitrosylation of secondary amines may be taken into account.
Kozlik
P
P
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Baehler
M
M
Puentener
C
C
Zerbe
O
O
Bigler
L
L
Altorfer
H R
HR
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006863:Hydrogen-Ion Concentration; D009603:Nitroso Compounds / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*
D009603:Nitroso Compounds; C440780:mono-N-desethylamiodarone; D000638:Amiodarone