Pharmacokinetics of 2-methoxyphenylmetyrapone and 2-bromophenylmetyrapone in rats

The pharmacokinetics of two 2-substituted phenylmetyrapone analogues, 2-met hoxyphenylmetyrapone (2-MPMP) and 2-bromophenylmetyrapone (2-BrPMP), develo ped as potential adrenal imaging agents, were investigated in conscious mal e rats following an intravenous dose of 25 mg/kg. Arterial blood samples (0 .25 ml) were collected at various intervals for up to 7 h after dose and su bjected to reversed-phase HPLC analysis. flood concentrations versus time p rofile for each compound was determined and the pharmacokinetic parameters calculated using the model-independent approach. Blood concentrations of 2- MPMP declined biexponentially with mean initial (t(1/2 alpha)) and terminal (t(1/2 beta)) half-lives of 3.6 and 23.1 min, respectively. The correspond ing area under the curve (AUC(0-infinity)) was 159.3 mu g.min/ml, the total blood clearance (Cl) was 158.3 ml/min and the volume of distribution (V-d) was 5.2 1. Two metabolites of 2-MPMP, namely 2-hydroxyphenylmetyrapone (2- OHPMP) and 2-methoxyphenylmetyrapone N-oxide (2-MPMP-NO), were detected in the blood and their elimination from blood was almost parallel to that of t he parent compound. The maximum blood concentrations (C-max) of 2-OHPMP and 2-MPMP-NO were approximately 0.9 and 1.7 mu g/ml, respectively. Blood conc entrations of 2-BrPMP declined monoexponentially with a mean t(1/2 beta) Of 12.0 min. The pharmacokinetic parameters for 2-BrPMP were: AUG(0-infinity) , 193.7 mu g.min/ml; Cl, 131.7 ml/min and V-d, 2.3 1. 2-Bromophenylmetyrapo ne N-oxide was the only one metabolite detected in the blood, its C-max and AUG(0-infinity) were 10.1 mu g/ml and 1690.0 mu g.min/ml, respectively.