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

Pierce, D. M.; Abrams, S. M. L.; Franklin, Richard A.

doi:10.1007/bf02455999

Cited by 9 publications

(1 citation statement)

References 12 publications

(13 reference statements)

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“…4 The drug is rapidly absorbed, but subject to extensive inter-subject variation in plasma concentration^.^'^ In the only previous report2 of the kinetics of indoramin in volunteers after multiple dosing, it was shown that plasma concentrations in 4 subjects dosed 3 times daily did not vary significantly over 2,4 or 6 weeks. However, this data did not include or allow a comparison between concentrations after multiple dosing and those predicted on the basis of concentrations seen after the first dose.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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

Pierce¹,

Franklin²,

Warrington³

1988

Biopharm & Drug Disp

Self Cite

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Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite

Pierce¹,

Abrams

Franklin³

1988

Eur J Clin Pharmacol

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Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0-24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0-24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.

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The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine

Pierce

Smith

Franklin³

1987

Eur J Clin Pharmacol

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Five poor metabolisers (PM) and seven extensive metabolisers (EM), of debrisoquine, all healthy volunteers, received 50 mg indoramin orally following an overnight fast. Plasma concentrations of indoramin and 6-hydroxyindoramin were determined by HPLC with fluorimetric detection. In PM subjects, mean values of Cmax (158 ng/ml) and AUC(0-24) (2556 ng X h X m-1) for indoramin were substantially elevated and t 1/2 beta (18.5 h) prolonged by comparison with values in the EM subjects (21.6 ng/ml, 151 ng X h X ml-1 and 5.2 h respectively). For 6-hydroxyindoramin, on the other hand, Cmax (12.4 ng/ml) and AUC (0-8) (47.5 ng X h X ml-1) in PM subjects were significantly lower than in the EM subjects (28.2 ng/ml and 94.7 ng X h X ml-1). There was a tendency to a higher incidence of side-effects in the PM group. Although the difference did not achieve statistical significance (0.1 greater than p greater than 0.05), all the PM subjects experienced sedation compared to only two in the EM group. Differences in blood pressure and pulse rate between the two groups were small. It is concluded that the oxidative metabolism of indoramin is subject to genetic polymorphism, which is probably under the control of the same gene locus as that influencing debrisoquine oxidation. The clinical consequences are discussed.

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

Cited by 9 publications

References 12 publications

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

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

Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite

The pharmacokinetics of indoramin and 6-hydroxyindoramin in poor and extensive hydroxylators of debrisoquine

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