scholarly journals Genotype-Guided Hydralazine Therapy

2020 ◽  
Vol 51 (10) ◽  
pp. 764-776 ◽  
Author(s):  
Kimberly S. Collins ◽  
Anthony L.J. Raviele ◽  
Amanda L. Elchynski ◽  
Alexander M. Woodcock ◽  
Yang Zhao ◽  
...  
Keyword(s):  
Resistant Hypertension ◽  
Antihypertensive Efficacy ◽  
Slow Acetylators ◽  
Slow Acetylator ◽  
Nat2 Genotype ◽  
Significant Relationships ◽  
Acetylator Status ◽  
Hydralazine Hydrochloride ◽  
Personalized Approach ◽  
Consistent Direction

<b><i>Background:</i></b> Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. <b><i>Summary:</i></b> There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. <b><i>Key Messages:</i></b> NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of <i>NAT2</i> genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

scholarly journals Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

1991 ◽  
Vol 24 (2) ◽  
pp. 111-114 ◽  
Author(s):  
Benedito Barraviera ◽  
Paulo Câmara Marques Pereira ◽  
Jussara Marcondes Machado ◽  
Maria Julia de Souza ◽  
Carlos Roberto G. Lima ◽  
...  
Keyword(s):  
Glutathione Reductase ◽  
Reductase Activity ◽  
Serum Levels ◽  
Slow Acetylators ◽  
Slow Acetylator ◽  
A Value ◽  
Acti Vity ◽  
Glutathione Reductase Activity ◽  
Glutathione Reductase Deficiency ◽  
Glucose 6 Phosphate Dehydrogenase

The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females) aged 17 to 58 years. Twenty one (53.84%) of the patients presented a slow acetylatingphenotype and 18(46.16%) a fast acetylating phenotype. Glucose-6-phosphate- dehydrogenase (G6PD) acti vity was decreased in 5(23.80%) slow acetylators and in 4(22.22%) fast acetylators. Glutathione reductase activity was decreased in 14 (66.66%) slow acetylators and in 12 (66.66%) fast acetylators. Serum levels of free and total sulfadoxin Were higher in slow acetylator (p < 0.02). Analysis of the resultspermitted us to conclude that serum sulfadoxin levels are related to the acetylatorphenotype. Furthermore, sulfadoxin levels were always above 50 µg/ml, a value considered therapeutic. Glutathione reductase deficiency observed in 66% of patients may be related to the intestinal malabsorption of nutrients, among them riboflavin, a FAD precursor vitamin, inpatients with paracoceidioidomycosis.

A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Hyounggyoon Yoo ◽  
Sang Chun Ji ◽  
Joo-Youn Cho ◽  
Sang-Heon Kim ◽  
Jihoon G. Yoon ◽  
...  
Keyword(s):  
Pilot Study ◽  
Slow Acetylators ◽  
Nat2 Genotype

Phase I/II dose-escalation trial of amonafide for treatment of advanced solid tumors: Genotyping to optimize dose based on polymorphic metabolism

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2503-2503 ◽  
Author(s):  
J. G. Kuhn ◽  
H. A. Burris ◽  
S. F. Jones ◽  
D. W. Hein ◽  
N. T. Willcutt ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Topoisomerase Ii ◽  
Nat2 Genotype ◽  
Primary Endpoints ◽  
Acetylator Status ◽  
Acetylator Genotype ◽  
Tumor Measurements ◽  
Tumor Types ◽  
Dose Levels

2503 Background: Amonafide (AMF), a synthetic imide derivative of naphthalic acid, is a topoisomerase II inhibitor and is subject to polymorphic metabolism based on acetylation genotype. AMF is extensively metabolized by N-acetyltransferase 2 (NAT2) to N- acetylamonafide (AAMF) which has activity nearly equipotent to AMF. In our phase I evaluation, we observed a correlation between NAT2 genotype, AMF/AAMF pharmacokinetics and toxicity (J Clin Oncol 22 [14S]: 2023, 2004). Patients (pts) with slow (S) acetylator genotype tolerated higher doses than those with rapid/intermediate (R/I) acetylator genotype. The present Phase II portion was designed to prospectively determine the dose of AMF based on NAT2 genotype and focused on selected tumor types. Methods: NAT2 genotyping of genomic DNA from blood samples was done prospectively to determine acetylator status of each pt. AMF was administered IV weekly x 3 q4wk, escalation range 320 to 400 mg/m2 for R/I and 400 to 500 mg/m2 for S acetylators. Primary endpoints: safety, MTD, tumor measurements or sustained decreases in tumor markers. Results: Total 47 pts (21 M/26 F), median 66 yr, PS 0–2, acetylator status R/I (26), S (21) with ovarian (11) or prostate (9), breast (8), colon (4) cancers (CA) and other common tumors refractory to therapy were treated; 30 of 47 pts were dosed based on prospective genotyping. Of these 30 pts, 17 were R/I acetylators: no toxicity at 320 mg/m2 AMF in 7/11 pts and manageable myelosuppresion in 4/11 pts observed days 15–21 of cycle but not dose-limiting (DLT); DLT in 3/6 pts at 400 mg/m2. In the 13 S acetylators: at 400 mg/m2 no DLT in 8 pts; DLT in 2/5 pts treated at 500 mg/m2. Other side effects included nausea/vomiting, fatigue and anemia. Of all 47 pts, biologic activity was seen in 6 pts: 3/9 prostate CA (decreased PSA), 2/11 ovarian CA (decreased CA125) and 1/1 GIST (decreased lymph nodes). Conclusions: MTD determined to be 320 mg/m2 in R/I and 400mg/m2 weekly x 3q 4 weeks in S acetylators, respectively, supporting hypothesis that AMF dosing based on prospective NAT2 genotyping may allow for dose optimization based on drug metabolism and result in better tolerance. Phase II assessments at the MTD dose levels are currently ongoing for prostate cancer. No significant financial relationships to disclose.

Lack of association between slow acetylator status and spontaneous lupus erythematosus

1990 ◽  
Vol 48 (2) ◽  
pp. 208-213 ◽  
Author(s):  
Cyrus R Kumana ◽  
Maureen M Y Chan ◽  
Kee-Lam Wong ◽  
Raymond W S Wong ◽  
Maybelle Kou ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Slow Acetylator ◽  
Acetylator Status

Studies on N-Acetyltransferase (NAT2) Genotype Relationships in Emiratis: Confirmation of the Existence of Phenotype Variation among Slow Acetylators

2017 ◽  
Vol 81 (5) ◽  
pp. 190-196 ◽  
Author(s):  
Mohammad M. Al-Ahmad ◽  
Naheed Amir ◽  
Subramanian Dhanasekaran ◽  
Anne John ◽  
Yousef M. Abdulrazzaq ◽  
...  
Keyword(s):  
Slow Acetylators ◽  
Phenotype Variation ◽  
Nat2 Genotype

P1.11 TRUE ANTIHYPERTENSIVE EFFICACY OF SEQUENTIAL NEPHRON BLOCKADE IN PATIENTS WITH RESISTANT HYPERTENSION AND CONFIRMED MEDICATION ADHERENCE

2013 ◽  
Vol 7 (3-4) ◽  
pp. 113
Author(s):  
H.B. Beaussier ◽  
F.M. Michael ◽  
F.C. Coudore ◽  
M.B. Briet ◽  
S.P. Peyrard ◽  
...  
Keyword(s):  
Medication Adherence ◽  
Resistant Hypertension ◽  
Antihypertensive Efficacy

scholarly journals NAT2 gene polymorphisms in three indigenous groups in the Colombian Caribbean Coast region

2014 ◽  
pp. 148-153
Author(s):  
Isis Arias ◽  
Nelly Lecompte ◽  
Lila Visbal ◽  
Iliana Curiel ◽  
Enio Hernández ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Drug Induced ◽  
Allelic Discrimination ◽  
Slow Acetylator ◽  
Indigenous Groups ◽  
Acetylator Status ◽  
Allelic Distribution ◽  
High Prevalence ◽  
Nat2 Gene ◽  
Pcr Method

Objective: To study the NAT2 gene polymorphisms 481T, 590A and 857A in the Chimila, Wiwa and Wayuu indigenous groups of the Colombian Caribbean to determine the frequencies of the allelesNAT2*4, NAT2*5, NAT2*6, and NAT2*7 and to determine the types of acetylators present in these populations. Methods: A total of 202 subjects were studied: 47 Chimila, 55 Wiwa, and 100 Wayuu. The polymorphisms were idenjpgied using a real-time PCR method for allelic discrimination designed using Taqman of Applied Biosystems. Results: The following alleles were found at the highest frequency in the following groups: the NAT2*4 allele (wild type) in the Wayuu group (55.3%), the NAT2*5 allele in the Wiwa group (34.5%), and the NAT2*7 allele in the Chimila group (24.2%). A higher frequency of the rapid acetylator status was found in the Wayuu group (31.3%) and Chimila group (29.5%) compared with the Wiwa group (12.7%). The intermediate acetylator status distribution was very similar in all three groups, and the frequency of the slow acetylator status was higher in the Wiwa group (32.7%) compared with the Chimila and Wayuu groups (20.5% and 21.2%, respectively). Conclusion: The results demonstrated the allelic distribution and pharmacogenetic differences of the three groups studied and revealed the most frequent acetylator status and phenotype. Because of the high prevalence of slow acetylators, a greater incidence of tuberculosis (TB) drug-induced hepatotoxicity is predicted in these populations, with a higher frequency in the Wiwa group.

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