Current concerns regarding inhalation exposure to Mn, a component from oxidation of the gasoline antiknock agent MMT, have stimulated interest in developing kinetic tools for describing the inhalation and combined inhalation/oral route kinetics of Mn. Kinetic approaches were integrated kinetic for (1) bulk tissue Mn kinetics and (2) hepato-intestinal control of oral-route Mn uptake into a integrated model structure connecting systemic and oral Mn. Linkages were developed between the hepato-intestinal and systemic tissues in order to evaluate differences in hepatic processing of orally absorbed Mn and systemic Mn. The integrated, unified model described the uptake, net absorption, and elimination of ingested Mn and the elimination kinetics of iv administered (systemic) Mn by treating Mn arriving at the liver from systemic versus portal blood differently. Hepatic extraction of orally absorbed Mn in rats predicted through simulation of the oral uptake data was 19, 54, and 78% at dietary exposures of 1.5, 11.2, and 100 ppm, respectively. In contrast, hepatic extraction of systemic Mn predicted through simulation of elimination kinetics iv tracer Mn was much less, 0.004, 0.005, or 0.009% at dietary levels of 2, 10, and 100 ppm, respectively. These differences in hepatic processing of blood Mn derived from different dose routes need to be accounted for in more complete PK models for Mn that are intended to support human health risk assessments.