Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure

Garcés-Eisele, Solón Javier; Cedillo-Carvallo, Beatriz; Reyes-Núñez, Virginia; Estrada-Marín, Larisa; Vázquez-Pérez, R.; Juárez-Calderón, M.; Guzmán-García, M.; Dueñas‐González, Alfonso; Ruı́z-Argüelles, Alejandro

doi:10.1111/jcpt.12155

Cited by 13 publications

(6 citation statements)

References 52 publications

(102 reference statements)

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“…In previous in vitro metabolic experiments using SMZ as a substrate, NAT2 * 5, * 6, and * 7 showed lower Vmax values than that of NAT2 * 4, but only NAT2 * 7 showed higher affinity for SMZ with lower Km compared with NAT2 * 4 (Olivera et al, 2007;Garces-Eisele et al, 2014), consistent with our current study. Additionally, NAT2 * 5 and * 6 alleles result in lower N-acetyltransferase activities toward SMZ compared with NAT2 * 7 (Walraven et al, 2008), and carriers of NAT2 * 5 and * 6 were categorized as USAs in the current study.…”

Section: Discussionsupporting

confidence: 91%

“…Our study showed that genotypes could be categorized into the USA phenotype in N-acetylation of HLZ, PZ, and SMZ by hierarchical clustering analysis. In a previous work, the pharmacokinetics of oral HLZ were found to be dependent on the NAT2 genotype during pregnancy (Han et al, 2019), and SA status was shown to be associated with clinical blood pressure and 24-h blood pressure after HLZ treatment in patients with resistant hypertension (Garces-Eisele et al, 2014). Therefore, the * 6/ * 6, * 6/ * 7, and * 7/ * 7 genotypes must be clearly distinct from the SA group, and this categorization may further improve individualization of HLZ treatment.…”

Section: Discussionmentioning

confidence: 94%

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Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Fukunaga

Kato²,

Okusaka³

et al. 2021

Front. Genet.

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Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 94%

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Fukunaga

Kato²,

Okusaka³

et al. 2021

Front. Genet.

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“…The three studies above suggest that evidence supports an association between acetylator phenotype or genotype and hydralazine concentrations. Similar findings were observed in other populations: Asian, African American, British, Kenyan, Mexican, Native Hawaiian, and Pacific Islanders (Table 2) [50-60]. Thus, a consistent and significant relationship between acetylator status and hydralazine concentration exists across a spectrum of populations.…”

Section: Effects Of Predicted Nat2 Activity On Hydralazine Concentratsupporting

confidence: 84%

Genotype-Guided Hydralazine Therapy

et al. 2020

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Background: 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. Summary: 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. Key Messages: 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 NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

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“…We explored gestational age, body weight, demographics, baseline hemodynamics, and concomitant medication dosage, but did not find an explanation for this unexpected finding. A study in healthy nonpregnant volunteers demonstrated that higher hydralazine dose was needed for NAT2 rapid acetylators to achieve comparable hydralazine AUC, as with the slow acetylators . A large study in nonpregnant subjects showed that rapid acetylators did not achieve adequate therapeutic effect with oral hydralazine, suggesting that NAT2 acetylation status might be important in pharmacodynamic response to oral hydralazine .…”

Section: Discussionmentioning

confidence: 99%

Effect of N‐Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy

Han

Ryu

Cusumano

et al. 2019

The Journal of Clinical Pharma

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Hydralazine, an antihypertensive agent used during pregnancy, undergoes N‐acetylation primarily via N‐acetyltransferase 2 (NAT2) to form 3‐methyl‐1,2,4‐triazolo[3,4‐a]phthalazine (MTP). To characterize the steady‐state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5‐25 mg every 6 hours) in mid‐ (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady‐state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n = 6) or slow acetylators (SAs, n = 6) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight‐adjusted hydralazine apparent oral clearance (70.0 ± 13.6 vs 20.1 ± 6.9 L/h, P < .05), lower dose‐normalized area under the concentration‐time curve (AUC; 1.5 ± 0.8 vs 5.9 ± 3.7 ng·h/mL, P < .05), lower dose‐normalized peak concentrations (0.77 ± 0.51 vs 4.04 ± 3.18 ng/mL, P < .05), and larger weight‐adjusted apparent oral volume of distribution (302 ± 112 vs 116 ± 45 L/kg, P < .05). Furthermore, the MTP/hydralazine AUC ratio was ∼10‐fold higher in the RA group (78 ± 30 vs 8 ± 3, P < .05) than in the SA group. No gestational age or dose‐dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.

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Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure

Abstract: Comparable hydralazine exposures (differences in AUC0-inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full-powered 2 × 2 crossover study.

Cited by 13 publications

References 52 publications

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity

Genotype-Guided Hydralazine Therapy

Effect of N‐Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy

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