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

Abstract

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.

The significance of QT interval in drug development

“…At a pharmacokinetic level, the metabolism of a number of QTc prolonging drugs, especially the neuroleptics, antidepressants and cardiovascular agents, is predominantly under the control of CYP2D6, a major drug metabolizing enzyme that is polymorphically expressed in the population. These include sertindole [44], thioridazine [45], risperidone [46], indoramin [47], nortriptyline [48] and terikalant [49]. The QTc interval prolongation following the administration of terikalant has been shown to correlate with CYP2D6 metabolic capacity [49].…”

Metabolites of Antihypertensive Drugs

“…As an a-adrenoceptor antagonist, this metabolite is approximately equipotent with the parent drug (Pierce et al 1987a). Pierce et al (1987b) examined the pharmacokinetics of a single oral dose of indoramin 50mg in 9 healthy volunteers. The mean Cmax, AVC and t,;, values of the parent drug were 22.4 J,Lg/L, 127 J,Lg/ L· hand 4.1 h, respectively.…”

Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

“…A single study reported that the systemic exposure of the · 1 -receptor antagonist indoramin was approximately 17 times higher in CYP2D6 PMs [49]. In this study, The ratios are calculated from a combined group of wt/*3 and *2/*3 genotypes.…”