Human pharmacokinetics of cadralazine: A new vasodilator

Hauffe, Suzanne; Dubois, J.P.; Imhof, P

doi:10.1007/bf03189745

Cited by 9 publications

(5 citation statements)

References 6 publications

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“…The elimination of cadralazine from plasma followed first order kinetics, with a mean half-life of 2.4 h. Assuming complete absorption, the total plasma clearance of cadralazine is 286 mlfmin. This agrees perfectly with findings from a human study with non-labelled cadralazine [8], which showed a mean half-life of 2.3 h and a total plasma clearance of 295 ml/rnin, The administered radioactive dose was rapidly excreted in urine and faeces. There was no sign of retention, since recovery was virtually complete after 3-4 days ( Table I).…”

Section: Discussionsupporting

confidence: 81%

“…Elimination half-life, area under the curve (AUC) and total plasma clearance were calculated according to the methods given in [8].…”

Section: Pharmacokinetic Evaluationmentioning

confidence: 99%

“…The kinetics of cadralazine (I) in rat and man are linear [7,8]. About 65-75% of an oral dose is excreted unchanged in urine of man [8].…”

Section: Introductionmentioning

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].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 81%

“…Elimination half-life, area under the curve (AUC) and total plasma clearance were calculated according to the methods given in [8].…”

Section: Pharmacokinetic Evaluationmentioning

confidence: 99%

“…The kinetics of cadralazine (I) in rat and man are linear [7,8]. About 65-75% of an oral dose is excreted unchanged in urine of man [8].…”

Section: Introductionmentioning

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].…”

Section: Introductionmentioning

confidence: 99%

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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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“…A recent study in rats substantiated the assumption that the slow onset and long duration of the pharmacological effect of cadralazine is closely related to the distribution pattern of this active metabolite in blood vessels, a target tissue of antihypertensive vasodilator drugs (9). In subjects with normal renal function, cadralazine is mostly eliminated from plasma in the unchanged form by the renal route: 60-80% of the oral dose is recovered in urine (7,12). The concentrations of the apparent hydrazino metabolite (unchanged compound plus its possible hydrazones) in plasma are low, 1-5% of those of cadralazine (7).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily

Marichal

Brunel

Lecaillon³

et al. 1992

European Journal of Drug Metabolism and Pharmacokinetics

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Since the hydrazino-pyridazine metabolite of cadralazine, CGP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment. The creatinine clearance (CLcr) of patients ranged from 10 to 60 ml/min. The concentrations of cadralazine in plasma and urine, and of CGP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLcr = 10 ml/min. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient, the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The t1/2 of CGP 22 639 was about twice the t1/2 of the unchanged drug. In patients whose CLcr ranged from 19-37 ml/min the mean accumulation factor of apparent CGP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent CGP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 ml/min appears to be suited to take into account the pharmacokinetics of CGP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLcr < 40 ml/min: 10 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

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