title: Dietary administration in rodent studies distorts the tissue deposition profile of lanthanum carbonate; brain deposition is a contamination artefact?
abstract: Lanthanum carbonate is a non-calcium phosphate binder used to control hyperphosphataemia in patients with chronic kidney disease who are undergoing dialysis. Ultrastructurally, lanthanum ions are too large to traverse the tight junctions in the blood-brain barrier, yet tissue distribution studies using dietary administration have reported low concentrations in rodent brain, raising concern about accumulation. To investigate this, tissue lanthanum concentrations were measured in rats given the same lanthanum carbonate dose via powdered diet or oral gavage (838 and 863 mg/kg/day). Additional rats were dosed intravenously with lanthanum chloride (0.03 mg/kg/day), a route enabling much higher plasma lanthanum concentrations. After 28 days, median lanthanum concentrations in liver, bone, kidney and heart showed a direct relationship with those in plasma (highest after intravenous and lowest after dietary dosing). In contrast, brain concentrations were dramatically higher after dietary administration (< or =500 ng/g), compared to the other routes (LLOQ of 11 ng/g). An identical skewed pattern was noted for skin, a tissue readily contaminated in powdered diet studies. These data indicate that brain deposition is a contamination artefact caused by transfer of lanthanum from cranial skin to brain as animals are manipulated during autopsy. Dietary administration should be avoided in distribution studies of trace elements due to the high contamination risk.
authors.affiliation: Shire Pharmaceutical Development Ltd., Hampshire International Business Park, Chineham, Basingstoke, UK. sdamment@shire.com
authors.forename: Stephen J P
authors.initials: SJ
authors.lastname: Damment
authors.forename: Alan G
authors.initials: AG
authors.lastname: Cox
authors.forename: Roger
authors.initials: R
authors.lastname: Secker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D007275:Injections, Intravenous; D007811:Lanthanum / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D009928:Organ Specificity; D051381:Rats; D014018:Tissue Distribution
chemical_list: C028521:lanthanum chloride; C119467:lanthanum carbonate; D007811:Lanthanum