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

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 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). RESULTS AND DISCUSSION: 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. WHAT IS NEW AND CONCLUSION: 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.

Isoniazid is not a lead compound for its pyridyl ring derivatives, isonicotinoyl amides, hydrazides, and hydrazones: a critical review.

The relationships between structure, disintegration and antituberculotic in vitro activity were studied for over 200 derivatives of isonicotinic acid hydrazide (isoniazid, INH). Conclusive evidence reflects that many compounds do not withstand the in vitro conditions. A pH dependant partial hydrolysis to INH occurs in the case of hydrazones, in analogy to well-known benzoic acid esters. Hydrazides and amides are cleaved into isonicotinic acid. In general, antimycobacterial potencies drop against INH except for two outliers probably with additional unspecific toxicity of their residues. Analyzing the complexity and heterogeneity of molecular events, trends linked to hydrolysis are found when structural features are clustered. Hammett sigma constants correlate to pK(a) values possessing a twofold descriptive meaning: (i) the cardinal increase of partial positive charge of the reaction center towards nucleophilic water attack and (ii) the ionization crucial for mycobacterial cell permeation through porins or lipid barriers. We review the literature concluding that many so-called "novel leads" are nothing else than precursors of an INH-based scaffold. In addition, INH ring-substitution or analogous backbones never achieve the efficiency of INH, itself a prodrug, which accumulates in Mycobacterium tuberculosis in form of its intrabacterial active principle(s) to which it is an optimal transport vehicle, evidencing that INH is not a promising lead compound at all.