Enzymatic dealkylation of aminopyrine (pyramidon) and other alkylamines.

Many drugs which are alkylamines undergo dealkylation in the body. For example aminopyrine (2), ephedrine (3), codeine (4), meperidine (5, S), methylamphetamine (7), and mephobarbital (8, 9) are all demethylated in ti~o. The removal of ethyl groups has been demonstrated with quinacrine,’ and an unusual t,ype of dealkylation, the loss of a B-chloroethyl group, occurs in the biotransformation of N-dibenzyl-/3-chloroethylamine (Dibenamine) (10). In spite of the importance of dealkylation in drug metabolism little is known concerning the biochemical mechanism responsible for the removal of the alkyl groups: whether one or a number of enzyme systems are responsible for the dealkylation of various alkylamines; the relationship between structure of alkylamines and their resistance to dealkylation; and finally what function, if any, the dealkylating enzymes serve in normal metabolic processes. Preliminary studies by Taggart, Poet, and Brodie2 have shown that aminopyrine (Pyramidon, dimethyl-4-aminoantipyrine) is demethylated to 4-aminoantipyrine on incubation with slices or homogenates of rabbit liver. The present communication presents further studies on the enzymatic dealkylation of aminopyrine and related alkylamines. It will be shown that the dealkylation enzyme system is located in the microsomes of liver cells and requires both oxygen and reduced triphosphopyridine nucleotide. Evidence will be presented that the methyl groups removed from aminopyrine are converted to formaldehyde and that the ethyl group removed from the monoethyl analogue is converted to acetaldehyde. Mater&&-Monomethyl-4-aminoantipyrine (henceforth referred to as MMAP) was kindly donated by Dr. Tainter of the Sterling-Winthrop Re-