Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats

Abstract

The toxicokinetics of manganese (Mn) was investigated in male and female rats either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg), or following a single oral dose of methylcyclopentadienyl manganese tricarbonyl (MMT) (20 mg MMT/kg or 5.6 mg Mn/kg). The plasma concentrations of manganese were quantified by atomic absorption spectrophotometry (AAS). Upon iv administration of MnCl2, manganese rapidly disappeared from blood with a terminal elimination t(1/2) of 1.83 h and CL(s) of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.9e(-4.24t) + 2.1e(-0.44t). Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (T(max) = 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT resulted in a delayed T(max) (7.6 h), elevated C(max) (0.93 μg/ml), and prolonged terminal t(1/2) (55.1 h). The rats receiving MMT had an apparent clearance (CL/F = 0.09 L/h kg) about 37-fold less than did those who were dosed with MnCl2. Accordingly, the area under the plasma concentration-time curves (AUC) of manganese in MMT-treated rats was about 37-fold greater than that in MnCl2-treated rats. A gender-dependent difference in toxicokinetic profiles of plasma manganese was also observed. Female rats displayed a greater AUC than that of male rats. Although the apparent volume of distribution of manganese was similar in both sexes, the apparent clearance in males was about twice that observed in females. The results indicated that after oral administration, the MMT-derived manganese displayed higher and more prolonged plasma concentration-time profiles than MnCl2-derived manganese. Thus, MMT-derived manganese appeared likely to accumulate in the body following repeated exposure.