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Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure
Author(s) -
GarcésEisele S. J.,
CedilloCarvallo B.,
ReyesNúñez V.,
EstradaMarín L.,
VázquezPérez R.,
JuárezCalderón M.,
GuzmánGarcía M. O.,
DueñasGonzález A.,
RuizArgüelles A.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12155
Subject(s) - hydralazine , pharmacokinetics , pharmacology , pharmacogenetics , genotype , population , active metabolite , valproic acid , genotyping , medicine , chemistry , epilepsy , blood pressure , biochemistry , environmental health , psychiatry , gene
Summary What is known and objective Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N ‐acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT 2 activity as deduced from their genotype. Methods An open label non‐randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20–45 years with a body mass index 22·2–26·9 which were classified as fast or slow acetylators after genotyping 3 SNP s that cover 99·9% of the NAT 2 variants in the Mexican population. Blood samples were collected predose and serially post‐dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra‐high performance liquid chromatography ( UPLC ) coupled to tandem mass spectroscopy ( MS / MS ). Results and discussion The AUC 0–48 h and C max of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT 2 genotype‐adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT 2 genotype ( AUC 0–48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; C max 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co‐administration of 83 or 182 mg of hydralazine. What is new and conclusion Comparable hydralazine exposures (differences in AUC 0–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.