Absorption, Distribution and Excretion of Tacrolimus(FK506) in the Baboon.

Abstract

The absorption, distribution and excretion of tacrolimus (FK506) was studied in the baboon after intravenous (i.v.) and oral administration of 14C-labeled FK506 (14C-FK506) at respective dose levels of 1 and 10 mg/kg. 1. After i.v. injection of 14C-FK506, both total radioactivity and FK506 were eliminated bi or tri-exponentially from the body. The whole blood levels of radioactivity were higher than those in the plasma, and were almost the same as the FK506 levels in the whole blood, which were much higher than those in the plasma. Model-independent pharmacokinetic parameters of FK506 in the whole blood were as follows: elimination half-life (T1/2), 12.3 hours; total body clearance, 0.265 L/h·kg; and volume of distribution at steady state, 3.93 L/kg. After oral administration, the parameters were as follows: T1/2, 10.4 hours; maximal blood concentration (Cmax), 190 ng/ml; time to reach Cmax, 2 hours; and area under the concentration-time curve (AUC0-∞), 2007 ng·h/ml. The bioavailability of radioactivity and FK506 was 7.0 and 5.1% respectively. The levels of radioactivity and FK506 were much lower in the plasma than those of the whole blood at FK506 level less than 250 ng/ml in the whole blood. 2. Tissue distribution of radioactivity was studied at 1, 24 and 120 hours after dosing with 14C-FK506. After i.v. injection, the radioactivity in all tissues collected was higher than that in the plasma 1 hour after injection, and was highest in the lungs, liver, pancreas, and small intestine. Radioactivity decreased gradually and was not detected in almost any tissues 120 hours after injection, except that maximal radioactivity in the large intestine was observed at 24 hours after injection. After oral administration, the radioactivity was detected in a limited number of the tissues such as thymus, liver, spleen, pancreas, bone marrow, and alimentary tract 1 hour after dosing and was not observed in almost any tissues 120 hours after dosing. The radioactivity in the body was mainly excreted in the bile to the feces after both administrations. 3. For 240 hours after administration of 14C-FK506, 5 and 86% of the dosed radioactivity were excreted in the urine and feces, respectively, after i.v. injection, and 4 and 79% after oral administration. The majority of radioactivity dosed was excreted in the urine and feces during the first 72 hours after both administrations.