Amantadine acetylation may be effected by acetyltransferases other than NAT1 or NAT2

Abstract

Amantadine is a drug with a primary amino group, and consequently a likely candidate for metabolism by acetylation. This study assessed the possibility that a person's polymorphic (NAT2) acetylator phenotype could be used to predict the extent of amantadine acetylation. Thirty-eight normal, healthy volunteers were NAT2 acetylator phenotyped with sulfapyridine. Of the six fastest (75-86%) and six slowest (34-40%) sulfapyridine acetylators, two and three, respectively, had acetylamantadine present (18-338 µg) in the 8-h urine collection. There was no correlation between NAT2 acetylator phenotype and amantadine acetylation (p < 0.5), and no difference in the total urine amantadine excreted over 8 h between acetylators and nonacetylators (28.3 ± 9.7 vs. 30.4 ± 9.6 mg, respectively, mean ± SD). Acetylamantadine represented 0.1-1.5% (median 0.5%) of urinary drug content over 8 h. Our data confirm that amantadine is acetylated in humans and demonstrate for the first time that the extent is not correlated with NAT2 acetylator phenotype. Parallel in vitro enzyme studies indicate the possibility that neither NAT1 nor NAT2 is responsible for acetylation of amantadine.Key words: amantadine, acetylation, conjugation, drug metabolism.