A review of the clinical pharmacokinetics and metabolism of the α₁-adrenoceptor antagonist indoramin

Abstract

1. The α₁-adrenoceptor antagonist indoramin is rapidly and extensively absorbed after oral administration, but with only low to moderate bioavailability (8-24% median) from the tablet (Baratol®). Although plasma protein binding is high (72-86%), the drug is widely distributed into tissues (with median V_z 6.3.7.71/kg after i.v. dosage).

2. Elimination of indoramin is rapid in most healthy volunteers, with median plasma clearances of 18-26ml/min per kg, after i.v. dosage. Elimination occurs principally by metabolism, the major route being indole 6-hydroxylation, followed by sulphate conjugation of 6-hydroxyindoramin. The faecal route of excretion predominates (45-50% of dose), with a further 35-40% in the urine.

3. Extensive variation in single-dose oral pharmacokinetics of indoramin is due largely to the existence of a poor metabolizer phenotype which co-segregates with that of debrisoquine.

4. On repeated administration (37.5 mg twice daily) to healthy volunteers, plasma concentrations of indoramin accumulate 3-4-fold above those anticipated from single-dose kinetics. However, steady state is achieved within the first week of dosing.

5. The pharmacokinetics of indoramin are substantially altered in the elderly. The oral AUC for a 50mg dose is increased approx. 5-fold and the t_1/2 2-5-fold.

6. Cirrhotic liver disease enhances bioavailability and decreases clearance, approx. 2-fold in each case for single oral and i.v. doses of 50mg and 0.15mg/kg respectively.

7. After oral indoramin C_max and AUC are both raised (58% and 25%, respectively, for a 50 mg dose) by co-ingested ethanol (0.5 g/kg). After i.v. indoramin, kinetics are unaffected by alcohol, but indoramin (0.175 mg/kg) slightly increases (26%) blood ethanol concentrations during the first hour after dosing.

8. The pharmacodynamics of indoramin appear to be related to the combined pharmacokinetics of the drug and its 6-hydroxylated metabolite, which contributes to the antihypertensive effect.