Interspecies differences in pharmacokinetics and metabolism of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)-propionamide: the role of N-acetyltransferase.
N-Acetyltransferase (NAT) is one of the major phase II enzymes involved in drug metabolism. Both species differences and polymorphism are observed in NAT expression. During the preclinical development of a novel selective androgen receptor modulator, S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S4), we also observed species differences in S4 metabolism due to the interaction between the deacetylation metabolite M1 and NAT, which converted M1 back to S4 both in vitro and in vivo. During incubation with human liver cytosol or rat liver S9 fraction in the presence of acetyl-CoA, more than 50% of M1 (2 microM) was converted back to S4, but this conversion was not observed in the incubation with dog liver S9 fraction or human liver microsome. In vivo pharmacokinetic experiments showed that M1 could be rapidly converted back to S4 in rats, but a similar conversion was not observed in dogs. When S4 was administered, the formation of M1 was only observed in dogs due to the absence of NAT expression. Simultaneous fitting of the concentration-time profiles of both S4 and M1 showed that more than 50% of S4 was deacetylated to M1 in dogs after i.v. administration of S4, whereas more than 80% of M1 was converted to S4 in rats after i.v. administration of M1. Considering the polymorphism in NAT expression, the interaction between M1 and NAT may raise concerns for drug-drug interactions during clinical applications of S4. The observed species differences suggested that interspecies scaling might not be applicable for predicting the metabolism and disposition of S4 in humans.
Gao
Wenqing
W
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Johnston
Jeffrey S
JS
Miller
Duane D
DD
Dalton
James T
JT
D000577:Amides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000728:Androgens / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009574:Nitro Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity
C508578:(S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide); D000577:Amides; D000728:Androgens; D007527:Isoenzymes; D009574:Nitro Compounds; D011994:Recombinant Proteins; C508582:S-3-(4-fluoro-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamid; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human