Genetic selection of volunteers and concomitant dose adjustment leads to comparable hydralazine/valproate exposure.
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 NAT2 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 SNPs that cover 99·9% of the NAT2 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).


CONCLUSIONS
The AUC0-48 h and Cmax 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 NAT2 genotype-adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0-48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 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.


CONCLUSIONS
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.
Clínica Ruiz Laboratorios, Puebla, México; Universidad Popular Autónoma del Estado de Puebla, Puebla, México.
S J
SJ
Garcés-Eisele
B
B
Cedillo-Carvallo
V
V
Reyes-Núñez
L
L
Estrada-Marín
R
R
Vázquez-Pérez
M
M
Juárez-Calderón
M O
MO
Guzmán-García
A
A
Dueñas-González
A
A
Ruiz-Argüelles
D000107:Acetylation; D000328:Adult; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008800:Mexico; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D013607:Tablets; D053719:Tandem Mass Spectrometry / Q000379:methods; D014635:Valproic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D013607:Tablets; D006830:Hydralazine; D014635:Valproic Acid; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
acetylator; bioavailability; genotype; phenotype