The features of hepatic enzyme induction with glutethimide in man.

Abstract

1 Sequential measurements of D‐glucaric acid excretion were made in six healthy volunteers before, during and after 3 weeks' daily medication with glutethimide 500 mg. 2 There was a rapid rise in D‐glucaric acid excretion within 2 days of starting medication and a rapid decline when it was stopped. 3 Antipyrine clearance and indocyanine green clearance were measured before and at the end of the 3 weeks' medication. 4 There was a 55% increase in antipyrine clearance but no change in indocyanine green clearance. 5 There was no correlation between antipyrine clearance and D‐glucaric acid excretion. 6 Glutethimide causes rapid enzyme induction in man without concomitant rise in hepatic blood flow.

The effect of acetylator phenotype on the disposition of aminoglutethimide.

“…AG markedly accelerates the metabolism of dexamethasone (after only 2 weeks' treatment, its clearance is increased by almost 300%) but has no effect on cortisol, oestrone, ndrostenedione or medroxyprogesterone acetate clearances (Santen et al, 1982b 2 days of starting medication (Jackson et al, 1978): it is not certain that AG induction was complete after a single week of treatment. Jarman et al (1983) Douglas & Nicholls (1972) found it to be the major urinary metabolite in man accounting for 4-25% of the administered dose after a single dose of AG.…”

“…These effects were rapid and clearly demonstrable following only 1 week of AG therapy. Studies showed that hepatic enzyme induction by glutethimide in man begins within 2 days of starting medication (Jackson et al, 1978): it is not certain that AG induction was complete after a single week of treatment. Jarman et al (1983) have identified hydroxylaminoglutethimide as an induced metabolite of AG on chronic dosing in three out of four patients and have speculated that formation of this inactive metabolite is the principal factor responsible for the decreased half-life of AG on chronic therapy.…”

D‐glucaric acid excretion in critical care patients‐comparison with 6 beta‐hydroxycortisol excretion and serum gamma‐glutamyltranspeptidase activity and relation to multiple drug therapy.

“…Numerous animal experiments and clinical pharmacological studies demonstrated that the effect of several enzyme inducers is reliably indicated by strongly increased GA excretion (Hildebrandt et al, 1975;Davis et al, 1974;Cunningham et al, 1974;Jackson et al, 1980;Mezey, 1976). Excellent correlation between GA excretion and antipyrine clearance has been presented recently in a collective of epileptics by Perucca et al (1984).…”

“…Due to this parallelism, GA has been extensively used as an indirect in vivo parameter of drug metabolism activity. The literature shows that GA mainly reflects the phenobarbitone type of induction (Cunningham et al, 1974;Davis et al, 1974;Garnham et al, 1970;Hildebrandt et al, 1975;Jackson et al, 1980;Kampf et al, 1980;Perry & Stamp, 1984;Roots et al, 1977). 6P-OHF is formed from cortisol via cytochrome P-450; the amount of this metabolite in a 24 h urine sample has been used to monitor the activity of oxidative drug metabolism (Berman & Green, 1971;Hildebrandt et al, 1975;Ohnhaus & Park, 1979;Roots et al, 1979).…”

Observations on the pharmacokinetics of low dose aminoglutethimide in patients with advanced breast cancer

“…Half-life and clearance rate studies performed in a further 6 patients at the start of therapy and later after 6 weeks of treatment demonstrated that the half-life of AG was shortened significantly and clearance rate increased significantly after 6 weeks of treatment. These data were interpreted as suggesting that AG, like glutethimide, may stimulate its own metabolism through hepatic microsomal enzyme induction (Jackson et al, 1978). …”