The absorption, distribution, metabolism and excretion of tacrolimus (FK506) were studied in the rat after intravenous (i.v.) and oral administration of ¹⁴C-labeled FK506 (¹⁴C-FK506).
1. After i.v. injection at a dose level of 1.0 mg/kg, the pharmacokinetic parameters of FK506 in the whole blood were as follows: elimination half life, 6.4 hours; total body clearance, 1.59 l/h ·kg; and volume of distribution at steady state, 11.8 l/kg. After oral administration at a dose level of 3.2 mg/kg, the parameters in the whole blood were as follows: maximal blood concentration (C_max), 41 ng/ml; time to reach C_max, 0.25 hour; and area under the concentration-time curve (AUC_0-24h), 255 ng·h/ml. Absorption of radioactivity and FK506 was 37 and 14%, respectively, calculated from the values of AUC0-24 h in the whole blood. Distribution of FK506 in the blood changed depending on its levels. The ratio of whole blood to plasma levels was more than 2.5 at less than the whole blood levels of 50 ng/ml but decreased above these levels.
2. Radioactivity was distributed throughout the body after i.v. injection of ¹⁴C-FK506 at a dose of 0.32 mg/kg. Radioactivity was highest in most of tissues at 5 minutes after injection, the first sampling point after injection, and the levels were higher than those in the plasma except that in the white fat, testis, cerebellum and cerebrum. At 72 hours after injection, radioactivity in most tissues decreased to less than 10% of the maximal concentrations except that in the cerebrum, testis and urinary bladder, in which about half of the concentration was detected. After oral administration at a dose of 1.0 mg/kg, radioactivity was distributed mainly in the gut and liver and was hardly detected in the other tissues.
3. During 72 hours after administration of ¹⁴C_ FK506 at a dose of 1.0 mg/kg, 8 and 95%of the dosed radioactivity were respectively excreted to the urine and feces after i.v. injection and 4 and 96% after oral administration. During 48 hours after i.v. injection to the bile duct-cannulated rats, 3, 8 and 82% of the dosed radioactivity were recovered in the urine, feces and bile, respectively, and 3, 6 and 35% during the same period after oral administration.
4. Less than 0.4% of the dosed radioactivity was excreted as unchanged FK506 in the urine, feces and bile, and the elution pattern of excreted radioactivity was very complex on high performance liquid chromatography and no major but many small radioactive peaks were observed. The major in vitro metabolite, 13-O-mono-demethylated metabolite, was detected in the urine, feces and bile but its portion to total radioactivity was very small.