High-performance liquid chromatographic separation of cadralazine from its potential metabolites and degradation products. Quantitation of the drug in human plasma and urine

Crolla, T.; Santini, Ferruccio; Visconti, M.; Pifferi, G.

doi:10.1016/0378-4347(84)80075-4

Cited by 5 publications

(1 citation statement)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacokinetic and metabolic studies were performed in rats, dogs, and man with I4C-labeled cadralazine as well as with the cold drug, the concentrations of which were determined by high-performance liquid chromatography (HPLC) (5,13,17,28,31,35).…”

Section: Biological Dispositionmentioning

confidence: 99%

Cadralazine

Dorigotti¹,

Ferni²

1987

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Cadralazine is a new and potent antihypertensive vasodilator drug (22) that has slow onset and long duration of action. It is well tolerated after long-term administration. Cadralazine is almost completely absorbed orally, its biotransfonnation is limited, and its hypotensive response is consistent. The research program that led to the development of cadralazine started about 16 years ago. The aim was to find an antihypertensive drug that would reduce vascular smooth muscle tone directly and specifically and would normalize the increased peripheral vascular resistance. At that time the only direct vasodilator drug available for the therapy of hypertension was hydralazine, and various approaches were in progress to discover new derivatives that would be more potent and safer than hydralazine.In our laboratory several hundred hydrazinopyridazines have been synthesized and submitted to pharmacological screening. During the early stage of the research some interesting structure-activity relations were detected, and a potent antihypertensive vasodilator, pildralazine, was selected (15,23,25). Subsequent chemical efforts were devoted to optimization of the pharmacological profile of pildralazine; they led to the discovery of cadralazine in 1978 (7,24). CHEMISTRYThe chemical name of cadralazine (ISF 2469) is ethyl 2-[6-[ethyl-(2-hydroxypropyl)amino]-3-pyridazinyl]hydrazinecarboxylate. The structural formula is shown in Fig. 1. The empirical formula is C,2H21N,03, and the molecular weight is 283.33. The product is a pale yellow, crystalline powder with a melting point range of 161" to 164°C. It is slightly soluble in water but freely soluble in acid. Cadralazine is a 6-substituted derivative of 3-hydrazino-pyridazine, which shares with hydralazine the structural features required for antihypertensive activity (19). However, the highly reactive hydrazino moiety in cadralazine is masked by the ethoxycarbonyl group. This structure prevents the hydrazine group from reacting with carbonyl groups, which are ubiquitous in the body. Moreover, the ethoxycarbonyl group protects the hydrazino moiety from being acetylated, a reaction that is a capacity-limiting step in the first-pass metabolism of hydralazine (34). 15.5

show abstract

Section: Biological Dispositionmentioning

confidence: 99%

Cadralazine

Dorigotti¹,

Ferni²

1987

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

show abstract

Pharmacokinetics of cadralazine in hypertensive patients

Leonetti¹,

Parini²,

Visconti³

et al. 1988

Eur. J. Drug Metab. Pharmacokinet.

View full text Add to dashboard Cite

Pharmacokinetics of cadralazine, urinary recovery of its putative active metabolite 3-hydrazino-6-aminopiridazine derivative (ISF 2405) and clinical effects were assessed in a placebo-controlled trial in 8 hypertensive in-patients, after acute oral administration of cadralazine. After a 2-week placebo-washout period, the protocol envisaged two consecutive days of monitoring of blood pressure and heart rate. On the first day a placebo tablet was given (9 am), while on the second day patients received a 30 mg cadralazine tablet in single-blind conditions. Blood and urine samples were obtained during the active drug day until 12 h after administration. Concentration of cadralazine in plasma and urine was detected by a specific HPLC method, while the metabolite ISF 2405 was detected in urine by a GC-MS method. Cadralazine caused gradual and long-lasting pressure decrease, statistically significant in comparison to placebo between 3 and 12 hours from drug intake, accompanied by a significant increase in heart rate. Cadralazine by oral route was promptly absorbed with a mean peak time of 1.3 h. Thereafter it followed a monoexponential decay curve, with a plasma half life of 3.1 h. The relative different bioavailability of oral cadralazine among patients was not correlated with cardiovascular changes. Urine recovery of unchanged drug after 12 h was high, reaching 67.3%, while concentration of metabolite ISF 2405 was about 1/1000 of parent compound.

show abstract

4 Pharmacologically Active Pyridazine Derivatives. Part 2

Heinisch

Kopelent‐Frank

1992

Progress in Medicinal Chemistry

View full text Add to dashboard Cite

High-performance liquid chromatographic separation of cadralazine from its potential metabolites and degradation products. Quantitation of the drug in human plasma and urine

Cited by 5 publications

References 3 publications

Cadralazine

Cadralazine

Pharmacokinetics of cadralazine in hypertensive patients

4 Pharmacologically Active Pyridazine Derivatives. Part 2

Contact Info

Product

Resources

About