Abstract
Aminopyrine(AM) has been used as a model substrate for investigation of drug metabolism. The major metabolic route is N-demethylation that was confirmed in liver microsomes. Another route, however, the oxidation of the 3-methyl group has not been confirmed in liver microsomes. AM and its metabolites including 3-hydroxymethyl-2-methyl-4-dimethylamino-1-phenyl-3-pyrazoline-5-one (AM-OH), which is a 3-hydroxylated metabolite, were separated on a reversed-phase(Cg) Radial-Pak column using a mobile phase of 30% methanol, 1% triethylamine and 69% water adjusted to pH 5.40 with acetic acid.By this rapid and simple method, AM hydroxylation was confirmed in liver microsomes of rats. The hydroxylation in control rat has two Km values (0.52 and 3.06 mM). Pretreatment of phénobarbital (PB) caused an induction of the hydroxylation activity and showed a low Km (0.51 mM) only. 3-Methylcholanthrene(3-MC) did not affect the activity and Km value of the hydroxylation. Similarly PB induced AM N-demethylation activity in agreement with former reports and changed the Km (low,0.80 and high,3.20 mM) into one Km (1.43 mM). Therefore AM hydroxylation as well as N-demethylation seems to be a PB-responding pathway.
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