234-80-0

The strength of hydralazine hydrochloride (I) 10 mg tablets, containing starch as an excipient, decreases significantly with time. An investigation to determine the basis for the drop in strength showed that starch exposed to the drug exhibited fluorescence at 414 nm. As model compounds IIIa and V, which contain a triazolophthalazinyl moiety, also fluoresce at about 414 nm, it is proposed that the emission is due to a triazolophthalazine derivative (IIIc) resulting from hydralazine hydrochloride and starch. Degradation of IIIc generates s-triazolo[3;4-a]phthalazine (IIIb), and a small amount of IIIb is detected in aged tablets. IIIc in aged tablets can be converted to IIIb by acid-catalyzed hydrolysis. The quantity of IIIb determined by HPLC amounts to most of the "missing" hydralazine hydrochloride. The reaction between hydralazine hydrochloride and starch is believed to cause the unexpected drop in the strength of hydralazine hydrochloride tablets.

The metabolite pattern of 1-hydrazinophthalazine hydrochloride (hydralazine hydrochloride, Apresoline) in the 0-24-h urine of hypertensive patients of both slow and fast acetylator phenotype, was studied after administration of an intercurrent oral dose of 14C-labelled hydralazine hydrochloride during chronic treatment with daily doses of either 50 mg b.i.d. or 100 mg b.i.d. hydralazine hydrochloride. Within either group of acetylator phenotype no statistically significant difference of the percentage yields of the individual metabolites between the low- and high-dose regimen could be found. The dominant urinary metabolite in both acetylator phenotypes was found to be 4-(2-acetylhydrazino)-phthalazinone (NAc-HPZ). In slow acetylators 18% and in fast acetylators 33% of the total radioactivity recovered in the urine was identified as NAc-HPZ. Another important metabolite assigned to the acetylation pathway is 3-hydroxymethyl-s-triazolo-[3,4-α] phthalazine (30H-MTP), excreted in conjugated form. Again in the urine of fast acetylators this metabolite was present in higher amounts (19%) than in slow acetylators (8.3%). A possible precursor of 30H-MTP, methyl-s-triazolo-[3,4-α]phthalazine (MTP) was found in low, but about equal, amounts in both acetylator phenotypes (slow: 3.3%; fast: 2.7%). An increased amount of MTP detected after enzymatic hydrolysis is probably due to conversion of hydralazine pyruvic acid hydrazone (HPPAH) into MTP under the applied reaction conditions. An acetylator phenotype related difference was also found for metabolites arising from pathways other than acetylation. s-Triazolo-[3,4-α]phthalazine (TP) was found to represent 0.9% of urinary radioactivity in slow acetylators and 6% in fast acetylators. Conditions of enzymatic hydrolysis reversed the pattern, there being higher amounts of TP in the urine of slow acetylators (10.9%) than in fast acetylators (8.4%). Also higher amounts of phthalazin-1-one (PZ) appeared in the urine of slow acetylators (4.3%) than in the urine of fast acetylators (1.8%). The assay of NAc-HPZ in urine of hypertensive patients will allow to determine their acetylation phenotypes more relevantly to hydralazine treatment than the conventional phenotyping tests can do.