Kinetics of Aluminum in Rats. II: Dose-Dependent Urinary and Biliary Excretion

• Published in: Journal of pharmaceutical sciences 1991-10, Vol.80 (10), p.946-951
• Main Authors: Xu, Zhi-Xin, Pal, Sudhakar M., Melethil, Srikumaran
• Format: Article
• Language: English
• Subjects: Aluminum - pharmacokinetics; Aluminum - urine; Animals; Bile - metabolism; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Half-Life; Kidney - metabolism; Liver - metabolism; Male; Medical sciences; Metals and various inorganic compounds; Rats; Rats, Inbred Strains; Toxicology; Ultrafiltration
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600801009

Previous iv studies from our laboratories have shown that the disappearance half-life of blood aluminum increased with dose. Experiments were initiated to determine if saturation of biliary and/or urinary excretion could be responsible for this dose-dependent behavior. Biliary aluminum excretion (0-12 h) accounted for < 1% of the injected amount at 0.1- and 1.0-mg/kg doses. During the same interval, urinary excretion accounted for 16.7 ± 2.66 and 8.85 ± 2.2% of administered dose at the low and high doses, respectively (p < 0.05); corresponding long term (0 to 13 or 22 days) urinary recoveries were 37.6 ± 3.67 and 28.4 ± 1.88% of the injected dose (p < 0.05), with most (66–70%) of the excretion occurring in the first 24h. This is consistent with many previous reports showing that urinary excretion is one major elimination pathway for aluminum. Both biliary and urinary clearances decreased with increasing blood aluminum concentration; the biliary and urinary clearance values at low concentrations (500–900 ng/mL) were approximately four- and threefold higher than the corresponding values at higher concentrations (10 000–12 000 ng/mL), respectively. It appears that this apparent saturability of biliary clearance may be due to concentration-dependent transfer of aluminum from blood to liver, rather than from liver to bile. In vitro ultrafiltration studies support the hypothesis that decreases in urinary clearance were due to decreased filterability of aluminum at the glomerulus as its blood concentration was increased. Dose dependency in the kinetics of blood aluminum appears to be due to differences in its tissue uptake and renal excretion caused by the formation of high molecular weight aggregates of aluminum at higher concentrations.