Pharmacokinetics of hydralazine, an antihypertensive and DNA-demethylating agent, using controlled-release formulations designed for use in dosing schedules based on the acetylator phenotype

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

“…A non‐randomized open label single arm pilot study was performed for the simultaneous determination of hydralazine and valproate PK parameters. Hydralazine was administered as a single dose in 24 h (one 83‐mg tablet for slow acetylators and one 182‐mg tablet for fast acetylators) and valproate in three doses of one 700‐mg tablet of controlled liberation every 8 h for both acetylator phenotypes …”

“…Hydralazine inhibits DNA methyltransferases DNMT1 and DNMT3a in the micromolar range, whereas valproate is a potent inhibitor of histone deacetylases in the range 0·4–1·5 m m . Due to the extensive first‐pass metabolism of hydralazine, primarily by the polymorphic arylamine N ‐acetyltransferase 2 (NAT2), the combination of hydralazine/valproate at doses of 182/700 mg and 83/700 mg is targeted at fast and slow acetylators, respectively . Two pathways have been proposed for hydralazine metabolism: direct acetylation, forming the metabolite 3‐methyl‐s‐triazolo (3,4‐a)‐phthalazine (MTP), and 3‐hydroxy‐MTP and acetylation of an unstable intermediate formed by a previous oxidation step, yielding N ‐acetylhydrazinophthalazinone (NAc‐HPZ) (see Fig.…”

PharmGKB summary

“…After oral dose, rapid acetylators display lower hydralazine plasma concentrations and area under the concentration-time curve (but no real difference in drug half life) compared to slow acetylators [119, 125, 127]. MTP/ hydralazine ratio can be used to divide a population into slow and rapid acetylators, with a lower and higher ratio, respectively [128].…”

“…In recent clinical trials in cancer patients, rapid acetylators (according to SMZ-acetylator phenotype) are given more than double the dose of hydralazine than that of slow acetylators. This resulted in similar plasma levels between the two acetylator groups in two studies [122, 127], but significantly higher plasma levels in rapid acetylators in a third study by the same group [121]. In a separate study examining blood pressure and cardiac output, using half doses of hydralazine in SMZ-slow acetylators was ineffective at changing peripheral resistance [130].…”

New insights and updated guidelines for epigenome-wide association studies

“…What is apparent is that there is a need for studies to test whether such an approach is feasible, potentially informative, and capable of generating enough of a "signal" of disease association that can be discriminated from the "noise" of the multiple variables that can confound these studies. Sources of variability need to be understood: There are many potential sources of variability that can affect EWAS data interpretation, including patient or disease issues (age (Heyn et al, 2012), sex (Sarter et al, 2005), and medications (Gonzalez-Fierro et al, 2011;Junien, 2006) or exposure histories), sample collection issues, nucleic acid purification protocols (Soriano-Tarraga et al, 2013), influences inherent to the experimental assays performed, and even the version and type of software analytical tools used to process and interpret the data generated. To account for these influences, it is recommended that metadata (data describing the information collected and generated) also be collected systematically and comprehensively.…”