Objective: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients.
Methods: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V).
Results: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure.
Conclusion: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.