Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats
Knowledge of dose linearity, plasma clearance, rate and extent of subcutaneous (SC) and intramuscular (IM) absorption of soluble aluminium (Al) citrate is considered a prerequisite for evaluation of toxicokinetic data obtained from SC or IM administration of Al adjuvants in medicinal products. Therefore, total Al plasma kinetics was investigated after SC, IM, and IV administration of single Al doses (36 and 360 µg/kg IM or SC; 30 and 300 µg/kg IV) given as citrate solution in rats. Control groups receiving vehicle (saline) were run in parallel to monitor background plasma Al levels over time resulting from dietary intake. Evaluation of Al plasma profiles was done by both non-compartmental analysis of baseline-corrected data and simultaneous model fitting to the raw data using a population kinetics approach. High and dose-independent total plasma clearance (6.6 mL/min/kg) was observed after IV administration corresponding to 60–82% of normal rat GFR. This supports the previous assumptions that parenterally administered Al citrate is more rapidly cleared from plasma than other Al species (e.g., chloride or lactate). Furthermore, plasma exposure of Al (Cmax and AUC0–inf) increased dose-proportionally at all administration routes. Fast and complete absorption of Al was observed at each dose level after both SC and IM administration (bioavailability estimates: 88 and 110%). Estimates for the first-order absorption rate constant ka correspond to absorption half-lives of 36 min (SC) and ≤ 13 min (IM). There was no increase in tissue Al content (whole bone and brain) after 36 µg/kg IM compared to control rats.
KeywordsAluminium Aluminium citrate Toxicokinetics Rat Intramuscular administration Subcutaneous administration
The authors thank Barbara Verhoeven for her technical assistance and Daniela Golomb for preparation of the treatment formulations.
The project was funded by the German Ministry of Health (ZMVI1-2515-FSB-772).
Compliance with ethical standards
Conflict of interest
Author Jennifer D. Oduro declares that she is employee at preclinics GmbH, a contract research organisation that has received payment for the conductance of the animal study. All the other authors declare that they have no conflict of interest.
All applicable international, national institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution (preclinics GmbH, Germany) at which the studies were conducted.
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