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 t1/2 of 1.83 h and CL8 of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.9e(-424t) + 2.1e(-0.44t). Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax = 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT resulted in a delayed Tmax(7.6 h), elevated Cmax (0.93 microg/ml), and prolonged terminal t1/2 (55.1 h). The rats receiving MMT had an apparent clearance (CL/F = 0.09 L/h x 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.

FIG. 1

Plasma concentration-time profiles of manganese in male Sprague-Dawley rats following an iv administration of MnCl₂ (6.0 mg Mn/kg). Plasma concentration of manganese was determined by AAS. The line indicates the best fit of a two-compartment model with first-order elimination from the central compartment to the observed data.

FIG. 2

Plasma concentration-time profiles of manganese in male Sprague-Dawley rats following a single oral dose of MnCl₂ (6.0 mg Mn/kg by gavage). Plasma concentration of manganese was determined by AAS. The terminal-phase parameters were calculated from 1–8 h for rat 1, 1–12 h for rat 2 and 3, and 0.5–12 h for rat 4. The value in parenthesis was not used in data analysis.

FIG. 3

Plasma concentration-time profiles of manganese in male or female Sprague-Dawley rats following a single oral dose of 20 mg/kg MMT (5.6 mg Mn/kg) in corn oil by gavage. Plasma concentration of manganese was determined by AAS. Data represent mean ± SD, n = 4 of each sex.

FIG. 4

Gender differences in (A) t_1/2, (B) AUC, and (C) CL/F in Sprague-Dawley rats following a single oral dose of 20 mg/kg MMT (5.6 mg Mn/kg) in corn oil by gavage. Data represent mean ± SD (n = 4–5). a) The comparison was made between MnCl₂ group and MMT group. b) The comparison was made between the male and female rats in the MMT-treated group. *p < 0.05; **p < 0.01.