Structure-Function Analyses of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 1

Walraven, Jason M.; Trent, John O.; Hein, David W.

doi:10.1080/03602530701852917

Cited by 46 publications

(37 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Human NAT1 and NAT2 loci are highly polymorphic, with more than 25 alleles identified in each locus. [28,29] Within this polymorphic population, different phenotypes have been identified for both forms, NAT1 and NAT2. As an important metabolizing en- zyme in humans, the polymorphism of human NAT expression, especially NAT2, raises concerns about drug-drug interactions during clinical use.…”

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

et al. 2010

View full text Add to dashboard Cite

Background: Activation of the sympathetic nervous system is an important feature in hypertension and congestive heart failure. A strategy for directly modulating sympathetic nerve function is to reduce the biosynthesis of norepinephrine (noradrenaline) via inhibition of dopamine-b-hydroxylase (DbH). Objective: To assess the safety, tolerability, and pharmacokinetics of etamicastat (BIA 5-453), a new DbH inhibitor, following repeated dosing. Methods: A double-blind, randomized, placebo-controlled study was conducted in healthy young male volunteers. Participants received once-daily doses of placebo or etamicastat 25, 50, 100, 200, 400, or 600 mg, for 10 days. Results: Etamicastat underwent N-acetylation to its metabolite BIA 5-961. Etamicastat and BIA 5-961 maximum concentrations were achieved at 1-3 and 2-4 hours, respectively, after dosing. Elimination half-lives ranged from 18.1 to 25.7 hours for etamicastat and 6.7 to 22.5 hours for BIA 5-961. Both etamicastat and BIA 5-961 followed linear pharmacokinetics. The extent of systemic exposure to etamicastat and BIA 5-961 increased in an approximately dose-proportional manner, and steady-state plasma concentrations were attained up to 9 days of dosing. Etamicastat accumulated in plasma following repeated administration. The mean observed accumulation ratio was 1.3-1.9 for etamicastat and 1.3-1.6 for BIA 5-961. Approximately 40% of the etamicastat dose was recovered in urine in the form of parent compound and BIA 5-961. There was a high variability in pharmacokinetic parameters, attributable to different N-acetyltransferase-2 (NAT2) phenotype. Urinary excretion of norepinephrine decreased following repeated administration of etamicastat. Etamicastat was generally well tolerated. There was no serious

show abstract

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

et al. 2010

View full text Add to dashboard Cite

show abstract

“…N-acetyltransferases exhibit different substrate specificities; in humans, isoniazid and sulfamethazine are efficiently N-acetylated by NAT2, whereas p-aminobenzoic acid is a substrate for NAT1 (Meyer, 1994;Stevens et al, 1999). It is recognized that human NAT1 and NAT2 loci are highly polymorphic, with more than 25 alleles identified in each locus (Hein et al, 2000a,b;Stanley and Sim, 2008;Walraven et al, 2008). As an important metabolizing enzyme in humans, the polymorphisms in human NAT expression, especially NAT2, raise concerns about drug-drug interactions related to drug metabolism during clinical use (Spielberg, 1996;Dorne, 2004).…”

mentioning

confidence: 99%

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

Loureiro¹,

Fernandes-Lopes²,

Bonifácio³

et al. 2013

Drug Metab Dispos

View full text Add to dashboard Cite

Etamicastat [(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride] is a reversible dopamineb-hydroxylase inhibitor that decreases norepinephrine levels in sympathetically innervated tissues. After in vivo administration, N-acetylation of etamicastat was found to be a main metabolic pathway. The purpose of the current study was to characterize the N-acetylation of etamicastat by N-acetyltransferases (NAT1 and NAT2) and evaluate potential species differences in etamicastat N-acetylation using a sensitive and specific liquid chromatographymass spectrometry assay. Marked differences in etamicastat N-acetylation were observed among the laboratory species and humans. After oral administration, the rat, hamster, and human subjects presented the highest rates of etamicastat N-acetylation, whereas almost no acetylation was observed in the mouse, rabbit, minipig, and monkey and no acetylation was observed in the dog.In in vitro studies, rats and humans showed similar acetylation rates, whereas no acetylation was detected in the dog. Studies performed with human recombinant NAT1 4 and NAT2 4 enzymes revealed that both were able to conjugate etamicastat, although at different rates. NAT1 had lower affinity compared with NAT2 (K m , 124.8 6 9.031 mM and 17.14 6 3.577 mM, respectively). A significant correlation (r 2 = 0.65, P < 0.05) was observed in a comparison of etamicastat N-acetylation by human single-donor enzymes and sulfamethazine, a selective substrate to NAT2. No correlation was observed with p-aminosalicylic acid, a NAT1 selective substrate. In conclusion, these results suggest that NAT2 and, to a lesser extent, NAT1 contribute to etamicastat N-acetylation. Furthermore, the high interspecies and intraspecies differences in N-acetylation should be taken into consideration when evaluating the in vivo bioavailability of etamicastat.

show abstract

“…Furthermore, there is clear role of bacterial NAT in overall Nacetylation of mesalazine, albeit its magnitude is controversial [22,23]. Also, the reported lack of differences in mesalazine response and tolerability between NAT1 genotypes [9,10] does not exclude differences in mesalazine pharmacokinetics, because differences in activity in NAT1 variants are limited [24,25] and pharmacodynamic parameters are less sensitive than pharmacokinetic parameters. Finally, in patients the degree of intestinal inflammation affects mesalazine pharmacokinetics [26].…”

Section: Discussionmentioning

confidence: 99%

Mesalazine pharmacokinetics and NAT2 phenotype

Lück

Kinzig

Jetter

et al. 2008

Eur J Clin Pharmacol

View full text Add to dashboard Cite

BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo.

show abstract

Structure-Function Analyses of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 1

Cited by 46 publications

References 48 publications

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

Safety, Tolerability, and Pharmacokinetics of Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor, in a Rising Multiple-Dose Study in Young Healthy Subjects

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

Mesalazine pharmacokinetics and NAT2 phenotype

Contact Info

Product

Resources

About