Physiological model for the pharmacokinetics of methyl mercury in the growing rat.
We describe a physiological pharmacokinetic model for methyl mercury and its metabolite mercuric mercury in the growing rat. Demethylation appears to occur in both host tissues and gastrointestinal flora with elimination dominated by biliary secretion of inorganic mercury and by transport of methyl mercury into the gut lumen followed by substantial bacterial metabolism. Biliary transport of both organic and inorganic mercury is modeled in terms of the known secretion of glutathione from the hepatic pool. At 98 days following an oral tracer dose of 203Hg-labeled methyl mercury chloride, 65% of the administered dose had been recovered in the feces as inorganic mercury and 15% as organic mercury. Urinary excretion is a minor elimination route, accounting for less than 4% of the dose as methyl mercury and 1% of the dose as inorganic mercury. Irreversible incorporation of the mercurials into hair is a significant route of elimination. Ten percent of the administered dose was contained in the hair shed during the 98 days and over 12% of the dose (almost 90% of the body burden) remained in the hair at the end of that time period. Apparent ingestion of hair by the rats during grooming represents a novel form of toxin recirculation. Transport of both chemical species between blood and tissues is bidirectional and symmetric with relatively slow movement into and out of the brain. Transport mechanisms for both mercurial species are discussed in the context of capillary transport physiology and the blood-brain barrier to small molecules and proteins.
Farris
F F
FF
Division of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20850.
Dedrick
R L
RL
Allen
P V
PV
Smith
J C
JC
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008627:Mercuric Chloride / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008767:Methylmercury Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D008767:Methylmercury Compounds; D008627:Mercuric Chloride; D005978:Glutathione