PaperIn vivo absorption of aluminium-containing vaccine adjuvants using 26Al
Abstract
Aluminium hydroxide (AH) and aluminium phosphate (AP) adjuvants, labelled with 26Al, were injected intramuscularly (i.m.) in New Zealand White rabbits. Blood and urine samples were collected for 28 days and analysed for 26Al using accelerator mass spectrometry to determine the absorption and elimination of AH and AP adjuvants. 26Al was present in the first blood sample (1 h) for both adjuvants. The area under the blood level curve for 28 days indicates that three times more aluminium was absorbed from AP adjuvant than AH adjuvant. The distribution profile of aluminium to tissues was the same for both adjuvants (kidney > spleen > liver > heart > lymph node > brain). This study has demonstrated that in vivo mechanisms are available to eliminate aluminium-containing adjuvants after i.m. administration. In addition, the pharmaco-kinetic profiles of AH and AP adjuvants are different.
References (15)
- D. Elmore et al.
The Purdue rare isotope measurement laboratory
Nucl. Instrum. Methods Phys. Res.
(1994) - A.T. Glenny et al.
The antigenic value of toxoid precipitated by potassium alum
J. Pathol. Bacteriol.
(1926) - S. Shirodkar et al.
Aluminum compounds used as adjuvants in vaccines
Pharm. Res.
(1990) - S.J. Seeber et al.
Solubilization of aluminum-containing adjuvants by constituents of interstitial fluid
Parenter. Sci. Technol.
(1991) - W. Frisell
Human Biochemistry
- G.H. Bell et al.
Textbook of Physiology and Biochemistry
- E.E. Selkurt
Physiology
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