Gene dose effect of NAT2 variants on the pharmacokinetics of isoniazid and acetylisoniazid in healthy Chinese subjects

Abstract

The results suggest that there is a conspicuous gene dose effect in the pharmacokinetics of INH and AcINH. This finding may be valuable in the personalized therapy of tuberculosis with INH.

A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy

“…The PK profile of the intermediate acetylator was hence a pure prediction. As for the previous PBPK models, we found a good correlation between the simulated and observed PK profiles ( 33 ) for INH ( Fig. 4A ) and AcINH ( Fig.…”

“…Since no comprehensive PK data set for both INH and all its considered metabolites was available in the literature, we combined data sets from several studies ( 30 – 32 ) and initially identified a set of kinetic and compound parameters for slow acetylators ( Tables 1 and 2 and Table S1 in the supplemental material). Further, data from an oral administration study were used to identify the intestinal absorption of INH ( 33 ). All other PK data considered ( 29 , 34 – 39 ) were used for subsequent model validation.…”

Arylamine N -acetyltransferase 2 genotype-dependent N -acetylation of isoniazid in cryopreserved human hepatocytes

“…Although the results of our study show significant differences in the N -acetylation of INH between rapid and intermediate acetylator hepatocytes both in vitro and in situ , the magnitude of the differences between rapid and intermediate acetylators were smaller than between intermediate and slow acetylators. Previous human in vivo studies have reported tri-modal distributions of INH N -acetylation reflective of rapid, intermediate, and slow NAT2 acetylator phenotypes24, 25, 26, 27, 28, 29.…”

Isoniazid metabolism and hepatotoxicity

“…GST polymorphisms, especially the genetic variants of GSTM1 and GSTT1 , have been extensively studied and are reported to associate with INH hepatotoxicity in clinic 123 , 124 . The GSTM1 -null genotype in an Asian population and the GSTT1 -null genotype in Caucasians have higher risks of liver injury caused by anti-TB drugs 83 , 125 , 126 , 127 . The null genotypes reduce the catalytic activity of the GST enzymes and hence lead to accumulation of the toxic metabolites that can attack the liver macromolecules.…”

“…The plasma levels of INH and AcHz are higher in slow acetylators than those in rapid acetylators, which contradicts previous findings 75 . Even though the acetylation rate of INH is slow in slow acetylators, the acetylation of AcHz is also slow 82 , thus leading to a higher accumulation of AcHz in slow acetylators 37 , 46 , 83 . The clearance rate of INH is also slower in slow acetylators than in rapid acetylators 38 , which also contributes to the accumulation of INH in slow acetylators.…”