Prediction of polymorphic N-acetylation of new drug candidates by correlation with human NAT1 and NAT2

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Due to interindividual variation in N-acetyltransferase 2 (NAT2) activity, pharmaceutical companies face the problem of polymorphic metabolism in drugs that are metabolized mainly or exclusively by this enzyme. An in vitro method has been developed to predict in vivo polymorphic N-acetylation at an early stage of drug development. Two new type 5H-2,3-benzodiazepine derivatives, Nerisopam (NER) with anxiolytic activity and GYKI47261 with antiepileptic activity, are metabolized mainly by N-acetylation in the rat and human. The selectivity of human N-acetyltransferases (NAT1,2) to form the acetylated metabolites has been investigated by correlation analysis. Twelve human liver samples were characterized for NAT1 and NAT2 phenotype based on their enzyme activity toward two selective NAT1 (p-aminobenzoic acid, PABA; p-aminosalicylic acid, PAS) and two selective NAT2 (sulfamethazine, SMZ; procainamide, PROC) substrates. Significant correlation was found between enzyme activities NAT1PABA/NAT1PAS and NAT2SMZ/NAT2PROC, respectively, and no correlation was observed comparing enzyme activities toward NAT1PABA/NAT2PROC. Enzyme activities using NER and GYKI 47261 as substrates were compared to activities obtained with NAT1 and NAT2 selective substrates, and the correlation coefficients were calculated. Good correlation was established between the rates of acetylation of the two drugs and that of the NAT2 selective substrate (NER/NAT2SMZ, r2 = 0.91, GYKI 47261/NAT2SMZ, r2 = 0.91). In contrast, no correlation was found between the rate of conjugation of the drugs and that of NAT1 selective substrate (NER/NAT1PABA, r2 = 0.022, GYKI 47261/NAT1PABA, r2 = 0.0004), suggesting polymorphic in vivo metabolism, since both drugs are acetylated preferably by NAT2. According to our results, correlation analysis based on in vitro acetylation activity may be used to predict in vivo polymorphic metabolism.

Original languageEnglish
Pages (from-to)17-22
Number of pages6
JournalDrug Development Research
Issue number1
Publication statusPublished - Aug 12 2002


  • N-acetyltransferases
  • Polymorphic acetylation

ASJC Scopus subject areas

  • Drug Discovery

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