B N Rehlaender1, M J Cho. 1. Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, 27599-7360, USA.
Abstract
PURPOSE: To better understand the pharmacokinetics of drugs compounds that bind endogenous antibodies METHODS: Three groups of mice with differing anti-fluorescein (FL) titers were established by empirically developed immunization protocols. These with two control groups were given intravenously [3H]-ethanolamine conjugate of FL (FL-EA). The latter was synthesized using isothiocyanate chemistry. Radioactivity in the circulation, and occasionally in peritoneal ascites, was monitored for 7 days. A group of mice was immunized with eosin Y and given FL-EA. Conversely, eosin Y conjugate of radiolabeled EA (EY-EA) was given to mice immunized with FL. These two groups represented animals of low affinity to probe haptens. The affinity was assessed by a precipitation procedure, while titer was determined by a standard ELISA. Dose of FL-EA varied over a 100-fold. RESULTS: On average, the three immunized groups showed a 1:13:85 ratio of anti-FL titer, with remarkably consistent levels within each group. Elimination rates of FL-EA from the serum of very high-titer mice and high-titer mice were similar, however, were substantially lower than that found in low-titer mice. The latter was in turn lower than that found in non- or mock-immunized mice. Serum of mice immunized with FL showed approximately 200-fold lower affinity towards EY-EA than FL-EA. In these mice and in mice immunized with eosin Y and given FL-EA, the elimination of the probe haptens was again fast, reminiscent of low-titer mice. Mice of either low titer or low affinity showed more rapid redistribution of the conjugate between serum and peritoneal fluid. In a group of mice with comparable anti-FL titer, elimination from serum was independent of dose over a 100-fold difference. The bi-phasic concentration-time profile observed was accommodated by a physiologically meaningful pharmacokinetic model incorporating two compartments in which antibody binding can occur. CONCLUSIONS: Monovalent antigenic substance cannot trigger immune clearance. As such, endogenous antibodies that recognize the molecule can serve as a carrier to result in a substantial decrease in clearance.
PURPOSE: To better understand the pharmacokinetics of drugs compounds that bind endogenous antibodies METHODS: Three groups of mice with differing anti-fluorescein (FL) titers were established by empirically developed immunization protocols. These with two control groups were given intravenously [3H]-ethanolamine conjugate of FL (FL-EA). The latter was synthesized using isothiocyanate chemistry. Radioactivity in the circulation, and occasionally in peritoneal ascites, was monitored for 7 days. A group of mice was immunized with eosin Y and given FL-EA. Conversely, eosin Y conjugate of radiolabeled EA (EY-EA) was given to mice immunized with FL. These two groups represented animals of low affinity to probe haptens. The affinity was assessed by a precipitation procedure, while titer was determined by a standard ELISA. Dose of FL-EA varied over a 100-fold. RESULTS: On average, the three immunized groups showed a 1:13:85 ratio of anti-FL titer, with remarkably consistent levels within each group. Elimination rates of FL-EA from the serum of very high-titer mice and high-titer mice were similar, however, were substantially lower than that found in low-titer mice. The latter was in turn lower than that found in non- or mock-immunized mice. Serum of mice immunized with FL showed approximately 200-fold lower affinity towards EY-EA than FL-EA. In these mice and in mice immunized with eosin Y and given FL-EA, the elimination of the probe haptens was again fast, reminiscent of low-titer mice. Mice of either low titer or low affinity showed more rapid redistribution of the conjugate between serum and peritoneal fluid. In a group of mice with comparable anti-FL titer, elimination from serum was independent of dose over a 100-fold difference. The bi-phasic concentration-time profile observed was accommodated by a physiologically meaningful pharmacokinetic model incorporating two compartments in which antibody binding can occur. CONCLUSIONS: Monovalent antigenic substance cannot trigger immune clearance. As such, endogenous antibodies that recognize the molecule can serve as a carrier to result in a substantial decrease in clearance.
Authors: K A Davies; K Erlendsson; H L Beynon; A M Peters; K Steinsson; H Valdimarsson; M J Walport Journal: J Immunol Date: 1993-10-01 Impact factor: 5.422