The effect of acetylator phenotype on the disposition of aminoglutethimide.

Abstract

1 Aminoglutethimide (AG) 500 mg was administered orally to four normal volunteers and eight patients undergoing treatment for metastatic breast cancer. In each subject the acetylator phenotype was established from the monoacetyldapsone (MADDS)/dapsone (DDS) ratio. 2 Acetylaminoglutethimide (acetylAG) rapidly appeared in the plasma and its disposition paralleled that of AG. 3 A close relationship (P < 0.01) was observed between the acetyl AG/AG and MADDS/DDS ratio suggesting that AG may undergo polymorphic acetylation like DDS. 4 AG half-life was 19.5 + 7.7 h in seven fast acetylators of DDS and 12.6 + 2.3 h in five slow acetylators and its apparent metabolic clearance was significantly (P < 0.01) related to the acetylAG/AG ratio. 5 Over 48 h the fast acetylators excreted 7.7 + 4.4% of the administered AG dose in the urine as unchanged AG as compared to 12.4 + 2.8% in slow acetylators. A much smaller fraction of the dose was excreted as acetylAG: 3.6 + 1.5% by fast and 1.9 ± 1.0% by slow acetylators respectively. 6 After 7 days treatment with AG at an accepted clinical dose regimen to the eight patients there were significant reductions in the half-lives of AG (P < 0.01) and acetylAG (P < 0.01) and a trend (0.1 > P > 0.05) towards reduction of the acetylAG/ AG ratio which became significant (P < 0.05) if the one patient on a known enzyme inducer was omitted. The mean apparent volume of distribution was not significantly (P > 0.1) altered but the mean apparent systemic clearance of AG was increased (P < 0.05). These changes are attributed to auto-induction of oxidative enzymes involved in AG metabolism.

Single-Dose and Steady-State Pharmacokinetics of Aminoglutethimide

“…However, AUC ratios above 1 have been reported previously (Coombes et aI., 1980(Coombes et aI., , 1982Stuart-Harris et aI., 1985). Our finding of a positive correlation between the initial clearance value of aminoglutethimide and the AUC ratio contrasts with the findings of Adam et al (1984) who reported a significant negative correlation coefficient. During phase I, these 2 patients had the smallest AUC ratios observed.…”

“…The elimination of this metabolite showed the same elimination rate constant as for aminoglutethimide, suggesting that production is the rate-limiting step in the elimination of this metabolite (Rowland and Tozer, 1980). The AUC ratios between N-acetylaminoglutethimide and aminoglutethimide obtained in the present study (table III) were in accordance with results obtained by Adam et al (1984), but our values showed a larger spread with some especially high values in phase 1. However, AUC ratios above 1 have been reported previously (Coombes et aI., 1980(Coombes et aI., , 1982Stuart-Harris et aI., 1985).…”

“…Similar data have been obtained by Murray et al (1979) and Thompson et al (1981) using a spectrophotometric assay, and more recently by Adam et al (1984) using a HPLC technique. Similar data have been obtained by Murray et al (1979) and Thompson et al (1981) using a spectrophotometric assay, and more recently by Adam et al (1984) using a HPLC technique.…”

“…Since no information is available regarding the clearance of N-acetylaminoglutethimide, it is not possible to calculate from our data the fraction of aminoglutethimide metabolised to the N-acetyl metabolite (Rowland and Tozer, 1980). Renal clearance of N-acetyJaminoglutethimide has been found to be identical to the renal clearance of aminoglutethimide (Adam et at, 1984). Values of N-acetylaminoglutethimide reported in the same investigations were 6.4% and 2.9%, respectively.…”

The use of cimetidine as a selective inhibitor of dapsone N‐ hydroxylation in man.

“…hydroxylamine is also toxic to human monoDapsone administered at 100 mg acutely has nucleocytes in vitro (Coleman et al, 1989) and often been used as a probe drug for the assessin granulopoiesis in vitro (Weetman et al, 1980). ment of acetylator phenotype (Adam et al, 1984;Horai et al, 1985;Hutchings et al, 1984). Swain et al (1983) noted that after a single dose of 150 mg no patients or volunteers suffered adverse effects.…”