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  • N acetylation by N acetyltransferase NAT is an


    N-acetylation by N-acetyltransferase (NAT) is an important metabolic pathway for some substances, and there are 2 functional NAT isoforms in humans—NAT1 and NAT2. Studies of etamicastat in healthy subjects showed an extensive N-acetylation of etamicastat to the inactive metabolite BIA 5-961, and a large interindividual variability in pharmacokinetic parameters of both etamicastat and BIA 5-961.23, 24, 25, 26 A pharmacogenetic investigation showed that such variability was dependent on differences in individual NAT2 genotypes (ie, single-nucleotide polymorphisms), leading to phenotypic differences in the N-acetylation metabolizing ability (ie, rapid or poor acetylator status).23, 24, 25, 26
    Patients and methods
    Discussion Sympathetic nervous system activation plays an important role in hypertension and congestive Canagliflozin failure physiopathology. An attractive therapeutic strategy is to modulate sympathetic function by reducing the biosynthesis of noradrenaline via inhibition of DβH. However, all attempts to develop DβH inhibitors have failed to date.18, 28 The current trial constituted the first study with etamicastat, a DβH inhibitor, in humans with essential arterial hypertension. In case of clinical development success, etamicastat would be the first medicine of a new antihypertensive class. The pharmacokinetic results of this study in hypertensive patients are consistent with those from studies of etamicastat in healthy subjects.23, 24, 25, 26 Similar to what occurred in healthy subjects, etamicastat was metabolized to its N-acetylated metabolite BIA 5-961. Etamicastat Tmax was 1 hour postdose. Thereafter, etamicastat plasma concentrations declined with a mean terminal t½ of 7 to 13 hours following the first dose and 19 to 28 hours following the last dose, which is very much in line with the results in Canagliflozin healthy subjects (9–15 hours following the first dose and 18–26 hours following the last dose) and consistent with a once-daily therapeutic regimen of etamicastat. Both etamicastat and BIA 5-961 appeared to follow less than dose-proportional pharmacokinetics, but the comparison of dose-normalized values of the main pharmacokinetic parameters showed that Cmax and AUC were not statistically different, in agreement with approximate linear pharmacokinetics found in single- and multiple-dose studies in healthy subjects.23, 24 The accumulation ratio was moderate for etamicastat (1.6–2.5) and small for BIA 5-961 (1.3–1.5). Steady-state plasma concentrations were reached very early, on the 2nd day of treatment, with both etamicastat and BIA 5-961. The NAT2 phenotype explained the large interindividual variability observed in main pharmacokinetic parameters. Humans express 2 functional NAT isoforms, NAT1 and NAT2. Whereas NAT1 is broadly distributed in human tissues, NAT2 is mainly expressed in the liver and erythrocytes. Both human NAT1 and NAT2 loci are highly polymorphic, with >25 alleles identified in each locus,29, 30 and such polymorphism responds for different phenotypes. NAT1 and NAT2 exhibit different substrate specificities. In in vitro studies, etamicastat N-acetylation showed a good correlation with the acetylation of sulfamethazine (a selective substrate to NAT2), but not with the acetylation of p-aminosalicylic acid (a selective substrate to NAT1), suggesting that etamicastat undergoes N-acetylation mainly through NAT2. The current study showed results consistent with these in vitro data and with results from previous studies in healthy subjects that showed a major influence of NAT2 phenotype on etamicastat pharmacokinetics.23, 24, 25, 26 The extent of systemic exposure to etamicastat, as assessed by AUC0–t, markedly differed between NAT2 poor and rapid acetylators. The extent of systemic exposure to etamicastat in poor acetylators was 2- to 3-fold higher than exposure seen in rapid acetylators and, inversely, rapid acetylators showed a 3- to 6-fold increase in systemic exposure to BIA 5-961. Similar to what occurred in previous studies in healthy subjects,23, 24 the distribution of rapid and poor NAT2 acetylators was not equal in all dose groups, and differences in the proportions of NAT2 rapid/poor acetylators complicated the interpretation of the results, namely the dose-proportionality assessment, and were a cause of large variability.