PHARMACOKINETICS OF TACROLIMUS IN LIVER-TRANSPLANT PATIENTS

Objective: To characterize the pharmacokinetics of the immunosuppressi ve agent tacrolimus (FK 506) in liver transplant patients. Method: Pat ients (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 conc entrations (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 max imum blood/plasma ratios (ranging from 13 to 114) we re strong (r = 0.65 and r = 0.73). Blood binding affects the dispositi on of tacrolimus, and plasma concentrations are indirectly and inverse ly related to red cell binding. The oral dose data for tacrolimus yiel ded a brief absorption lag time (t(lag), 0.39 hour), a variable first- order absorption rate constant (k(a) 415 +/- 3.0 hr(-1)), and consiste nt 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 pro vides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a majo r source of interpatient variation in the disposition of tacrolimus.