Studies on the metabolism of cadralazine in rat

Simonotti, L.; Zanol, Margherita; Parravicini, F.; Pifferi, G.

doi:10.1007/bf03189541

Cited by 11 publications

(4 citation statements)

References 7 publications

(6 reference statements)

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“…A possible compound that can be considered is the free 3-hydrazino-derivative, a metabolite which has been isolated from rat urine [6] and has been shown to be pharmacologically active [7]. Detailed metabolic studies of cadralazine in man have been undertaken and will be reported separately [8].…”

Section: Discussionmentioning

confidence: 99%

Human pharmacokinetics of cadralazine: A new vasodilator

Hauffe

Dubois

Imhof

1985

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetic profiles in plasma and the renal elimination of 2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)ethylcarbazate+ ++ were investigated in six healthy volunteers following single oral doses of 5, 10 and 20 mg of cadralazine. The study was run in a randomized change-over design experiment. Concentrations of cadralazine in plasma and urine were determined by a high-performance liquid chromatography method. Maximum plasma levels (Cmax) were reached between 0.25 and 1.0 h (tmax) after administration and ranged from 69.8 to 210.0 ng/g after the 5 mg dose, 148.9 to 333.3 ng/g after the 10 mg dose and 292.9 to 474.5 ng/g after the 20 mg dose. The corresponding area under the plasma concentration-time curve (AUC24hO) are 330, 621 and 1168 (ng/g). h. Mean renal elimination of the unchanged-drug ranged from 69 to 73% of the dose. Mean Cmax, AUC24hO and mean total renal elimination were linearly dose-related. An elimination half-life from plasma of about 2.5 h was observed for cadralazine. Estimations for the mean renal and total clearance range from 185 to 216 ml/min and 251 to 295 ml/min, respectively.

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Section: Discussionmentioning

confidence: 99%

Human pharmacokinetics of cadralazine: A new vasodilator

Hauffe

Dubois

Imhof

1985

European Journal of Drug Metabolism and Pharmacokinetics

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“…This value includes possible hydrazones of IV with endogenous aldehydes or ketones, because in the IDA method used such hydrazones are cleaved by acid treatment [12]. The formation of IV has also been observed in rats [9].…”

Section: Discussionmentioning

confidence: 99%

“…About 65-75% of an oral dose is excreted unchanged in urine of man [8]. From animal studies several minor metabolites are known, II-V [9] and VI-VIII [10]. For formulas see below.…”

Section: Introductionmentioning

confidence: 99%

Disposition and pharmacokinetics of cadralazine and individual metabolites in man

Schütz

Faigle

Küng

et al. 1985

European Journal of Drug Metabolism and Pharmacokinetics

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The absorption, biotransformation and elimination of the antihypertensive drug cadralazine, 2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)-ethylcarbazate , have been studied in two healthy male volunteers, following single 20 mg oral doses of the 14C-labelled preparation. Absorption was rapid and complete. In plasma total 14C-compounds reached maximum levels of 395 and 312 ng/g after 0.5 and 1.5 h in subject A and B, respectively. The levels rapidly declined to 3 and 6 ng/g after 24 h. Unchanged cadralazine constituted the major fraction, 72%, of the integrated plasma concentration (AUC, 0-24 h) of total radioactivity. As determined by an isotope dilution technique, about 1% of the AUC of plasma-14C was attributable to a pharmacologically active hydrazino-metabolite (IV) formed by decarbethoxylation and 2% to the acetylation product of the latter (V). Excretion of the radioactivity occured predominantly by the kidneys, 91 and 94% within 0-24 h in subject A and B. After 96 h 94 and 99% of the dose were found in the excreta. In the 0-48 h urine 73% of total 14C consisted of unchanged drug. The hydrazino-metabolite (IV) accounted for about 2% of urinary radioactivity, and two secondary products of the same pathway (II, V) for another 2%. Products of N-dealkylation (VI, VII) and C-oxidation (VIII) constituted together another 5%.

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“…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

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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

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Studies on the metabolism of cadralazine in rat

Cited by 11 publications

References 7 publications

Human pharmacokinetics of cadralazine: A new vasodilator

Human pharmacokinetics of cadralazine: A new vasodilator

Disposition and pharmacokinetics of cadralazine and individual metabolites in man

Cadralazine

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