Slow accumulation of cyclosporin metabolites as measured by specific and nonspecific cyclosporin RIA.

Blood cyclosporin concentrations were measured by radioimmunoassay (RIA) using nonspecific polyclonal and specific monoclonal antibodies in 32 kidney transplant patients. Kinetics of cyclosporin concentrations after transplantation (day 0-2) and after long-term dosage (day 7-month 6) were evaluated by nonlinear regression analysis. Elimination and accumulation kinetics were linear and in agreement with one- or two-compartment kinetics. Only in 3 cases were saturable Michaelis-Menten kinetics observed (Vm = 23 ng/ml h-1, Km = 636 ng/ml). Bioavailability was 0.72 as estimated from first-pass extraction. The median values (5-95% CI) for the elimination half-life of nonspecific RIA concentrations increased from 5 h (2.5-6.2) on day 2 after transplantation to 10 h (9.2-11) after long-term dosage. The specific monoclonal antibody data revealed an elimination half-life of 6.4 h (5.6-7.7) for parent cyclosporin, which was unchanged after multiple dosing. After month 6, the elimination half-life of specific monoclonal antibody data was significantly shorter (p = 0.03) than elimination half-life of nonspecific RIA concentrations (6.6 vs 9.1 h). In relation to blood concentrations measured by nonspecific polyclonal antibody RIA, the fraction of parent cyclosporin significantly decreased from 84 percent (49-90) to 30 percent (24-52) after long-term dosage as measured by specific monoclonal antibody (p = 0.01). It is concluded that metabolites of cyclosporin accumulate in a slow compartment and, after long-term cyclosporin administration, nonspecific RIA blood concentrations are mainly contributed by cyclosporin metabolites.