A review on the clinical pharmacokinetics of hydralazine.

INTRODUCTION: Hydralazine is a vasodilator used to treat hypertension, pre-eclampsia, and heart failure. The current article reviews the clinical pharmacokinetics (PK) of hydralazine, which can be useful for clinicians in optimizing its dose and dosing frequency to avoid adverse effects and unexpected interactions that could risk patients' lives. AREAS COVERED: This review has summarized the PK parameters for hydralazine after performing an extensive literature search. It includes 20 publications that were selected after applying eligibility criteria out of a pool of literature that was searched using Google Scholar, PubMed, Cochrane Central, and EBSCO databases. The included studies consisted of concentration vs. time profiles of hydralazine. If the PK data were not tabulated in the given study, the concentration vs. time profiles were scanned for the extraction of the PK data. The PK parameters were calculated by applying a non-compartmental analysis (NCA). EXPERT OPINION: The current review will aid clinicians in understanding hydralazine PK in different disease populations. This clinical PK data might also be helpful in the development of a pharmacokinetic model of hydralazine.

Case Study 11: Considerations for Enzyme Mapping Experiments-Interaction Between the Aldehyde Oxidase Inhibitor Hydralazine and Glutathione.

Often it may be convenient and efficient to address multiple research questions with a single experiment. In many instances, however, the best approach is to design the experiment to address one question at a time. The design of enzyme mapping experiments is discussed in this chapter, focusing on considerations pertinent to the study of aldehyde oxidase (AO) vs. cytochrome P450 metabolism. Specifically, a case is presented in which reduced glutathione (GSH) was included in an experiment with human liver S9 fraction to trap reactive metabolites generated from cytochrome P450-mediated metabolism of lapatinib and its O-dealkylated metabolite, M1 (question 1). The AO inhibitor hydralazine was included in this experiment to investigate the involvement of AO-mediated metabolism of M1 (question 2). The presence of GSH was found to interfere with the inhibitory activity of hydralazine. Consideration of the time-dependent nature of hydralazine inhibitory activity toward AO when designing this experiment could have predicted the potential for GSH to interfere with hydralazine. This case underscores the importance of clearly identifying the research question, tailoring the experimental protocol to answer that question, and then meticulously considering how the experimental conditions could influence the results, particularly if attempting to address multiple questions with a single experiment.

Genotype-Guided Hydralazine Therapy.

BACKGROUND: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. SUMMARY: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

Effect of N-Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy.

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n = 6) or slow acetylators (SAs, n = 6) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight-adjusted hydralazine apparent oral clearance (70.0 ± 13.6 vs 20.1 ± 6.9 L/h, P < .05), lower dose-normalized area under the concentration-time curve (AUC; 1.5 ± 0.8 vs 5.9 ± 3.7 ng·h/mL, P < .05), lower dose-normalized peak concentrations (0.77 ± 0.51 vs 4.04 ± 3.18 ng/mL, P < .05), and larger weight-adjusted apparent oral volume of distribution (302 ± 112 vs 116 ± 45 L/kg, P < .05). Furthermore, the MTP/hydralazine AUC ratio was ∼10-fold higher in the RA group (78 ± 30 vs 8 ± 3, P < .05) than in the SA group. No gestational age or dose-dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.

Hydralazine HCl rapidly disintegrating sublingual tablets: simple dosage form of higher bioavailability and enhanced clinical efficacy for potential rapid control on hypertensive preeclampsia.

BACKGROUND: Hypertensive disorders are the most common complication in pregnancy which can even lead to maternal mortality. Hydralazine hydrochloride (HHC), a direct-acting vasodilator, is intravenously used as the first-line therapy in controlling hypertension in pregnancy (preeclampsia). It suffers poor oral bioavailability (26%-50%) due to first-pass metabolism. OBJECTIVE: This work aims for the preparation of HHC rapidly disintegrating sublingual tablets of higher absorption rate, short onset of action, and higher bioavailability for rapid control on blood pressure (BP) in hypertensive emergencies especially preeclampsia. METHODS: HHC sublingual tablet mixtures were prepared using starch sodium glycolate and Pharmaburst as super disintegrants at three different levels by direct compression and were subjected to full in vitro evaluation; the drug bioavailability from the optimized sublingual tablet formula was assessed in comparison to conventional oral tablets in rabbits, and the clinical efficacy on controlling BP in induced preeclampsia like mouse model was also studied. RESULTS: The results indicated compatibility of the prepared tablet mixtures, good flow, and acceptable mechanical strength. Sublingual tablet formula containing Pharmaburst (7%) that showed fastest disintegration (21 seconds) and 100% drug release within 5 minutes was selected for further bioavailability and pharmacodynamic studies. The drug bioavailability was significantly increased with C max = 28.2767±4.61 µg/mL, AUC(0-α) = 52.85±3.18 µg.h/mL, and T max = 0.33±0.011 hour in comparison to 18.0633±23.2 µg/mL, 33.18±5.18 µg⋅h/mL, and 0.75±0.025 hour for conventional oral tablets. Results of pharmacodynamic studies proved significant rapid control on both systolic and diastolic BP to normal values within only 30 minutes without any significant difference from intravenous data. CONCLUSION: These results confirm the suitability of the prepared HHC sublingual tablets for use in rapid control on hypertensive crisis especially in pregnant women as an alternate to parenteral administration.

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.

Neuroprotective role of hydralazine in rat spinal cord injury-attenuation of acrolein-mediated damage.

Acrolein, an α,ß-unsaturated aldehyde and a reactive product of lipid peroxidation, has been suggested as a key factor in neural post-traumatic secondary injury in spinal cord injury (SCI), mainly based on in vitro and ex vivo evidence. Here, we demonstrate an increase of acrolein up to 300%; the elevation lasted at least 2 weeks in a rat SCI model. More importantly, hydralazine, a known acrolein scavenger can provide neuroprotection when applied systemically. Besides effectively reducing acrolein, hydralazine treatment also resulted in significant amelioration of tissue damage, motor deficits, and neuropathic pain. This effect was further supported by demonstrating the ability of hydralazine to reach spinal cord tissue at a therapeutic level following intraperitoneal application. This suggests that hydralazine is an effective neuroprotective agent not only in vitro, but in a live animal model of SCI as well. Finally, the role of acrolein in SCI was further validated by the fact that acrolein injection into the spinal cord caused significant SCI-like tissue damage and motor deficits. Taken together, available evidence strongly suggests a critical causal role of acrolein in the pathogenesis of spinal cord trauma. Since acrolein has been linked to a variety of illness and conditions, we believe that acrolein-scavenging measures have the potential to be expanded significantly ensuring a broad impact on human health.

Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance.

Aldehyde oxidase (AO) metabolism could lead to significant underestimation of clearance in prediction of human pharmacokinetics as well as unanticipated exposure to AO-generated metabolites, if not accounted for early in drug research. We report a method using cryopreserved human hepatocytes and the time-dependent AO inhibitor hydralazine (K(I) = 83 ± 27 µM, k(inact) = 0.063 ± 0.007 min(-1)), which estimates the contribution of AO metabolism relative to total hepatic clearance. Using zaleplon as a probe substrate and simultaneously monitoring the AO-catalyzed formation of oxozaleplon and the CYP3A-catalyzed formation of desethyzaleplon in the presence of a range of hydralazine concentrations, it was determined that >90% inhibition of the AO activity with minimal effect on the CYP3A activity could be achieved with 25 to 50 µM hydralazine. This method was used to estimate the fraction metabolized due to AO [f(m(AO))] for six compounds with clearance attributed to AO along with four other drugs not metabolized by AO. The f(m(AO)) values for the AO substrates ranged between 0.49 and 0.83. Differences in estimated f(m(AO)) between two batches of pooled human hepatocytes suggest that sensitivity to hydralazine varies slightly with hepatocyte preparations. Substrates with a CYP2D6 contribution to clearance were affected by hydralazine to a minor extent, because of weak inhibition of this enzyme. Overall, these findings demonstrate that hydralazine, at a concentration of 25 to 50 µM, can be used in human hepatocyte incubations to estimate the contribution of AO to the hepatic clearance of drugs and other compounds.

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

PURPOSE: The antihypertensive hydralazine has recently been repositioned as DNA demethylating for the epigenetic therapy of cancer. As the acetylator phenotype is the key determinant of its plasma levels, the dose of hydralazine needs to be adjusted for the acetylation status of patients. METHODS: The pharmacokinetics of orally administered hydralazine was evaluated in 26 healthy volunteers (13 slow and 13 fast acetylators) after a single dose of 182 mg administered as a controlled-release tablet. Plasma levels of hydralazine were analyzed in 85 cancer patients treated with this formulation at a dose of 83 mg/day and 182 mg/day for slow and fast acetylators, respectively. RESULTS: The C(max) and t(max) of hydralazine for fast acetylators were 208.4 ± 56.9 SD ng/ml and 2.8 ± 2.5 h, respectively. The corresponding results for slow acetylators were 470.4 ± 162.8 ng/ml, and 4.4 ± 3.1 h. Healthy volunteers who were fast acetylators had no clinically significant changes in blood pressure and heart rate or any other side-effect, however, slow acetylators had transient episodes of headache, tachycardia and faintness. Among 85 cancer patients that received either 182 mg or 83 mg of hydralazine daily, according to their acetylator status, the mean concentrations of hydralazine in plasma were 239.1 ng/ml and 259.2 ng/ml for fast and slow acetylators, respectively. These differences were not significantly different, p = 0.3868. CONCLUSIONS: The administration of dose-adjusted controlled-release hydralazine according to the acetylation status of cancer patients yields similar levels of hydralazine.

Terapia vasodilatadora / Vasodilator therapy

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Pharmacogenetics, race and global injustice.

This paper discusses the link between pharmacogenetics and race, and the global justice issues that the introduction of pharmacogenetics in pharmaceutical research and clinical practice will raise. First, it briefly outlines the likely impact of pharmacogenetics on pharmaceutical research and clinical practice within the next five to ten years and then explores the link between pharmacogenetic traits and 'race'. It is shown that any link between apparent race and pharmacogenetics is problematic and that race cannot be used as a proxy for pharmacogenetic knowledge. The final section considers the implications of the development of pharmacogenetics for health care systems in low- and middle-income countries.

Isosorbide dinitrate/hydralazine: its role in the treatment of heart failure.

Despite the advances in pharmacotherapy for heart failure due to reduced left ventricular function, mortality still remains high and many patients are hospitalized over time due to worsening heart failure symptoms. There is some experimental evidence that vasoconstriction and nitric oxide (NO) deficiency in the vasculature play a role in aggravating the symptoms of heart failure, especially in patients of African-American origin. Treatment with high doses of isosorbide dinitrate (ISDN) has been shown to increase symptom-free walking time, but tolerance to the hemodynamic effects of ISDN develops rapidly. Experimental data suggests that hydralazine, given concomitantly, attenuates the development of hemodynamic tolerance to ISDN and may increase bioavailability of NO in the vasculature. In a racially mixed population, treatment with a combination of ISDN and hydralazine reduced mortality compared to placebo to a nearly statistically significant extent in the first Vasodilator Heart Failure Trial (V-HeFT I) but was inferior to treatment with angiotensin-converting enzyme (ACE) inhibitor enalapril in the V-HeFT II study. Subgroup retrospective analysis of published data, however, suggested that ISDN/hydralazine had a substantial effect in black patients and was apparently as effective as treatment with the ACE inhibitor, enalapril, in the same population, but had a much smaller, if any, effect in white patients. A recent placebocontrolled study showed that in self-identified black patients with heart failure, ISDN/hydralazine, given in addition to current state-of-the-art pharmacotherapy for heart failure, reduces mortality and first hospitalizations due to heart failure and improves quality of life. The usefulness of ISDN/hydralazine in ethnic groups other than self-identified blacks is unknown at present and is considered off-label use. This review focuses on ISDN/hydralazine for the management of patients with heart failure due to left ventricular dysfunction and the adverse effects which may be encountered with therapy.

Lack of bioequivalence between different formulations of isosorbide dinitrate and hydralazine and the fixed-dose combination of isosorbide dinitrate/hydralazine: the V-HeFT paradox.

OBJECTIVE: To investigate whether the apparent discrepancy between the efficacy of the combination of isosorbide dinitrate (ISDN) and hydralazine demonstrated in the first V-HeFT trial (V-HeFT I) and that in V-HeFT II could be explained by pharmacokinetic differences in the study drug formulations, and to compare the pharmacokinetic profile of the fixed-dose combination of ISDN/hydralazine (FDC ISDN/HYD; BiDil) formulation used in A-HeFT with that of the V-HeFT study drug formulations. STUDY PARTICIPANTS AND METHODS: A bioequivalence study was performed (n = 18-19 per group) comparing the ISDN and hydralazine formulations used in V-HeFT I, V-HeFT II and A-HeFT in healthy volunteer men and women aged 18-40 years. In phase A of the study, subjects received a reference solution of hydralazine hydrochloride/ISDN (37.5mg/10mg) orally. Slow acetylators were identified and randomised into three groups in phase B to receive a single oral dose of identical amounts of hydralazine hydrochloride/ISDN (37.5mg/10mg) from either (i) a hydralazine capsule plus an ISDN tablet (the V-HeFT I formulation); (ii) a hydralazine tablet plus an ISDN tablet (the V-HeFT II formulation); or (iii) FDC ISDN/HYD (the A-HeFT formulation). Blood/plasma concentrations of hydralazine and ISDN were determined from the blood samples taken between 0 and 36 hours. RESULTS: In phase B, the maximum observed concentrations (C(max)) were 65.9 +/- 53.9, 28.2 +/- 15.8 and 51.5 +/- 54.3 ng/mL of unchanged hydralazine, and 23.1 +/- 12.3, 21.7 +/- 13.4 and 26.7 +/- 18.7 ng/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. The area under the blood/plasma concentration-time curve (AUC) values were 32.6 +/- 13.4, 23.3 +/- 15.1 and 32.6 +/- 18.5 ng x h/mL of hydralazine, and 24.4 +/- 9.0, 24.8 +/- 8.0 and 23.5 +/- 6.3 ng x h/mL of ISDN for the V-HeFT I, V-HeFT II and A-HeFT formulations, respectively. For comparison of bioequivalence, the C(max) and AUC were normalised to 65kg bodyweight, and point estimates and 90% confidence intervals of the C(max) ratios, AUC ratios and ratios of the AUC in phase B normalised for clearance by the AUC in phase A (AUCR) were calculated. The three formulations were not bioequivalent based on the C(max) and AUC comparisons. CONCLUSIONS: The blood concentrations of hydralazine obtained with the tablet formulation tested in V-HeFT II were markedly lower than those obtained with the capsule formulation tested in V-HeFT I or the FDC ISDN/HYD single tablet used in A-HeFT. The apparently modest effect on survival observed in V-HeFT II could be explained in part by the poor hydralazine bioavailability of the tablet preparation used in this trial. ISDN exposures were similar in the two trials. The ISDN-hydralazine formulation used in V-HeFT II was not bioequivalent to the formulation used in V-HeFT I or to the FDC ISDN/HYD that had demonstrated a significant survival benefit in A-HeFT.

BiDil (isosorbide dinitrate and hydralazine): a new fixed-dose combination of two older medications for the treatment of heart failure in black patients.

BiDil is a new fixed-dose combination of 2 older medications, isosorbide dinitrate (ISDN) and hydralazine. ISDN is an organic nitrate that is biotransformed into nitric oxide, a potent vasodilator. Hydralazine is believed to have both vasodilatory properties specific to the arteries and antioxidant properties, which address both the biochemical alterations in the failing cardiovascular system as well as the issue of nitrate tolerance. A drug regimen combining an NO stimulator (ISDN) with an antioxidant (hydralazine) favorably influences the nitroso-redox balance. Retrospective analyses of previous heart failure (HF) clinical trials comparing the combination of ISDN and hydralazine with placebo and enalapril, respectively, demonstrated a benefit in the black population, setting the precedent for a race-based therapeutic study, the African-American Heart Failure Trial (A-HeFT). A-HeFT examined the use of BiDil added to standard HF therapy in blacks with New York Heart Association functional class III and IV HF. BiDil demonstrated a 43% reduction in mortality when compared with placebo. As a result, current evidence-based treatment guidelines recommend that the addition of ISDN and hydralazine in black patients with moderate to severe HF optimized on standard therapy be considered. BiDil is currently indicated for the treatment of HF as an adjunct to standard therapy in black patients. The use of BiDil for black patients with mild disease or in nonblack patients with HF has not been studied. Future clinical trials involving an ethnically and clinically diverse population of patients would further define the role of combined ISDN and hydralazine in the treatment of HF.

Hydralazine reduces the quantal size of secretory events by displacement of catecholamines from adrenomedullary chromaffin secretory vesicles.

The effects of the antihypertensive agent hydralazine (1 to 100 nmol/L) on the exocytotic process of single adrenal chromaffin cells have been studied using amperometry. Hydralazine does not reduce the frequency of exocytotic spikes but rapidly slows the rate of catecholamine release from individual exocytotic events by reducing the quantal size of catecholamine exocytosis. Confocal and standard epifluorescence microscopy studies show that hydralazine rapidly accumulates within secretory vesicles. The blockade of the vesicular H+ pump with bafilomycin A1 inhibits hydralazine uptake. Experiments with permeabilized cells show that hydralazine displaces catecholamines from secretory vesicles. The drug also displaces vesicular Ca2+, as shown by fura-2 microfluorimetry. These data suggest that hydralazine acts, at least partially, by interfering with the storage of catecholamines. These effects of hydralazine occurred within seconds, and at the tissue concentrations presumably reached in antihypertensive therapy; these concentrations are a thousand times lower than those described for relaxing vascular tissues in vitro. We proposed that these novel effects could explain many of the therapeutic and side effects of this drug that are likely exerted in sympathetic nerve terminals.

Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine.

1-Hydrazinophthalazine [hydralazine (HDZ)] is a hydrazine derivative that is a direct acting vasodilator effective in the treatment of essential hypertension. HDZ is biotransformed by the phase II conjugation enzyme N-acetyltransferase (NAT) forming acetyl HDZ, which spontaneously cyclized to the stable product 3-methyl-s-triazolo- [3,4-alpha]-phthalazine (MTP). Therapeutic use of HDZ has resulted in adverse side effects, specifically a drug-induced systemic lupus erythematosus. Slow acetylators are more likely than rapid acetylators to develop this toxicity. Bacteria expressing different levels of NAT were used to test the hypothesis that acetylation of HDZ decreases its mutagenic potential. The variation in NAT activities was confirmed by incubating bacterial cultures with HDZ, and the formation of MTP was monitored by HPLC. At 1.0 mg/ml HDZ, YG1029 (NAT overexpresser) produced 5.3 times the amount of MTP as TA100 (normal NAT expresser), and this production was linear for 20 hr. In the Salmonella mutagenesis assay, HDZ produced a dose- and strain-dependent increase in the number of revertants observed. Exposure to 4 mg HDZ/plate resulted in 1000 revertants in the overexpressing strain, YG1029, whereas both TA100 and TA100/1,8DNP6, which express normal levels and lack the NAT protein respectively, produced 1600 revertants. Colony hybridization analysis using probes for each of the six possible TA100 reverting mutations was performed to determine the nature of the mutations. The G:C to T:A transversion was the only mutation whose frequency was increased significantly by HDZ. Fifty-four percent of the induced vs. 25% of the spontaneous mutations were C to A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigations into a new antiarrhythmic substance Z-2-amino-5-chlor-benzophenon-amidin-hydralazin in humans.

Z-2-amino-5-chlor-benzophenon-amidin-hydralazin is a new chemical potential antiarrhythmic substance. The blood levels were investigated after different dosages and forms of administration in patients and volunteers. The determination of the substance can be performed by high-pressure liquid chromatography. In addition the pharmacokinetic parameters were calculated. The pharmacokinetic profile is similar in humans and animals.