Pharmacokinetics of 2-methoxyphenylmetyrapone and 2-bromophenylmetyrapone in rats.

ABSTRACT

The pharmacokinetics of two 2-substituted phenylmetyrapone analogues, 2-methoxyphenylmetyrapone (2-MPMP) and 2-bromophenylmetyrapone (2-BrPMP), developed as potential adrenal imaging agents, were investigated in conscious male 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 subjected to reversed-phase HPLC analysis. Blood concentrations versus time profile 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 (t1/2alpha) and terminal (t1/2beta) half-lives of 3.6 and 23.1 min, respectively. The corresponding area under the curve (AUC(0-infinity)) was 159.3 microg x min/ml, the total blood clearance (CI) was 158.3 ml/min and the volume of distribution (Vd) was 5.2 l. 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 the parent compound. The maximum blood concentrations (Cmax) of 2-OHPMP and 2-MPMP-NO were approximately 0.9 and 1.7 microg/ml, respectively. Blood concentrations of 2-BrPMP declined monoexponentially with a mean t1/2beta of 12.0 min. The pharmacokinetic parameters for 2-BrPMP were AUC(0-infinity), 193.7 microg x min/ml; Cl, 131.7 ml/min and Vd, 2.3 l. 2-Bromophenylmetyrapone N-oxide was the only one metabolite detected in the blood, its Cmax and AUC0-infinity were 10.1 microg/ml and 1690.0 microg x min/ml, respectively.