Pharmacokinetics of oral indoramin in elderly and middle-aged female volunteers

Norbury, H. M.; Franklin, Richard A.; Marrott, Pran; Warrington, S. J.

doi:10.1007/bf00544054

Cited by 13 publications

(3 citation statements)

References 9 publications

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“…The median systemic availability of indoramin from the tablet (24%) was identical to that derived from data in a U.S. study in 24 subjects (Leelavathi D, personal communication) but higher than the mean value of 8.3% reported previously by Norbury et al (1984) in only 5 subjects. On the basis of the revised figure, indoramin systemic availability is of an order comparable with that of verapamil (20%, McAllister and Kirsten 1982), labetolol (31%, Louis et al 1978), and propranolol (30%, Johnson and Reghrdh, 1976), but lower than that for atenolol (> 40%, Johnson and Reg~rdh, 1976) and prazosin (57%, Bateman et al 1979).…”

Section: Discussionsupporting

confidence: 73%

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Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects

Pierce¹,

Abrams

Franklin³

1987

Eur J Clin Pharmacol

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We have studied the pharmacokinetics and absolute systemic availability of indoramin (50 mg) given orally in solution or as a tablet with reference to intravenously administered drug (0.15 mg/kg) in 9 healthy volunteers. After intravenous administration the median apparent volume of distribution was 6.3 l X kg-1, plasma clearance was 20.0 ml X min-1 X kg-1, and terminal half-time was 4.1 h. When given by tablet indoramin was absorbed with moderate rapidity, with a median tmax of 1.5 h. The median systemic availability was 24%. After oral administration in solution the drug was more rapidly absorbed, with a median tmax of 1.0 h (p less than 0.01). The median systemic availability was 43% (15-85%). Plasma concentrations of an active metabolite, 6-hydroxyindoramin, after single oral doses in either dosage form, were of a similar order to those of unchanged drug and fell with similar rapidity. After intravenous administration, however, concentrations of the metabolite were negligible.

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Section: Discussionsupporting

confidence: 73%

“…After oral administration indoramin is subject to extensive first-pass metabolism (Draffan et al 1976), leading to somewhat low and variable plasma concentrations (Volans et al 1982;Norbury et al 1984). Its mean systemic availability (+ SD) in 5 middleaged female volunteers has been previously estimated at 8.3 + 2.9% (Norbury et al 1984).…”

mentioning

confidence: 98%

Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects

Pierce¹,

Abrams

Franklin³

1987

Eur J Clin Pharmacol

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“…Hemodynamic responses to vasodilators in patients with heart failure are related to baseline hemodynamic status, with greater increases in cardiac output occurring in patients with lower baseline values.13 This pattern of hemodynamic response, that is, predominant venodilating effect with systemic vasodilation more apparent only in patients with worse hemodynamics, is very similar to that observed with other venodilating agents, especially nit r a t e~.~~ The observed time course of action of indoramin with onset by 1 hour, peak effect at 2 hours, and waning of effects by 6 hours after a single dose is consistent with previous pharmacokinetic studies. 24 The effects of 1 week of dosing with indoramin are of interest. We observed sustained hemodynamic effects characterized by a reduction in mean systemic arterial pressure but with a greater concomitant reduction in cardiac output so that total systemic resistance actually rose.…”

Section: Discussionmentioning

confidence: 99%

Indoramin in heart failure: Possible adverse effects on hemodynamics and exercise capacity

Love

Galiè

Casebolt

et al. 1986

Clin Pharmacol Ther

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Indoramin is an alpha 1-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 12 patients with heart failure, before and after 1 week of indoramin dosing, 75 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 +/- 15.3 to 87.9 +/- 15.3 mm Hg (P less than 0.05) and pulmonary wedge pressure from 23.6 +/- 7.8 to 16.9 +/- 6.6 mm Hg (P less than 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 +/- 0.38 to 2.32 +/- 0.44 L/min/m2 (P less than 0.05) and total systemic resistance rose from 20.4 +/- 2.8 to 21.9 +/- 4.0 U (P less than 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 +/- 5.6 to 12.5 +/- 3.5 ml/min/kg (P less than 0.02). This limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodynamics during continuous dosing in these patients.

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Pharmacokinetics of indoramin and its 6‐hydroxylated metabolite after repeated oral dosing

Pierce¹,

Franklin²,

Warrington³

1988

Biopharm & Drug Disp

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The pharmacokinetics of indoramin and its active 6-hydroxylated metabolite have been studied in healthy male volunteers after repeated oral dosing with 37.5 mg twice daily for 2 weeks. Plasma concentrations of indoramin accumulated, on average, three to four-fold above those anticipated on the basis of the kinetics after the first dose, though steady state was achieved by the end of the first week and no further increase was observed after 2 weeks. The degree of accumulation was consistent between subjects, with a highly significant (p less than 0.001) correlation between the concentration 2 h after a single dose and the average steady-state concentration. Possible explanations for the accumulation of indoramin are discussed. Plasma concentrations of 6-hydroxyindoramin, in contrast, did not accumulate on multiple dosing. At steady state, concentrations of the metabolite, as represented by the AUC0-8h, were approximately 30-40 per cent of those of the unchanged drug. Since the two compounds are approximately equipotent the metabolite may accounts for 25 per cent of the hypotensive activity of indoramin during a typical clinical regime of 37.5 mg twice daily.

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Pharmacokinetics of oral indoramin in elderly and middle-aged female volunteers

Cited by 13 publications

References 9 publications

Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects

Pharmacokinetics and systemic availability of the antihypertensive agent indoramin and its metabolite 6-hydroxyindoramin in healthy subjects

Indoramin in heart failure: Possible adverse effects on hemodynamics and exercise capacity

Pharmacokinetics of indoramin and its 6‐hydroxylated metabolite after repeated oral dosing

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