Distribution kinetics of FK-506, a novel immunosuppressant, after intravenous administration to rats in comparison with cyclosporin A

✍ Scribed by Kanji Takada; Hisato Usuda; Mamoru Oh-Hashi

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 588 KB
• Volume: 13
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510130506

✦ Synopsis

The distribution kinetics of a novel potent immunosuppressant, FK-506 (FK) has been studied in comparison with cyclosporin A (CyA) both in vivo and in vitro using blood specimens. The infusion studies on FK, 5.0mg kg-1 through the portal and femoral veins showed that the mean hepatic extraction ratio of FK was 27.9 per cent. The effect of clamping both the hepatic artery and the portal vein on the plasma disappearance profiles of FK, 5-0mgkg-', and CyA, 3.5mgkg-1 was studied. The plasma disposition kinetics of CyA was almost the same as in the normal rats. However, the plasma FK levels were about 10 times higher than those obtained in the control group rats. This difference is attributed to the restricted initial distribution of FK to the liver, because the volume of the initial distribution space, Vl, of FK was about 10 times smaller than that obtained in normal rats. In in vitro experiments, drug distribution was studied in blood samples (2.0 ml) spiked with FK or CyA, 1.0 pg ml-l. The plasma drug levels measured at 2 min after drug administration were 0.842kO.012 pg ml-' and 0-769kO.047 pgml-' for FK and CyA, respectively. The distribution volume in the blood compartment, V,, was determined by dividing the spiked amount of drugs with these plasma concentrations. The V, was 2.3850.04 ml for FK and 2.62tO.16 ml for CyA. There was no significant difference in V, between FK and CyA. The plasma free fraction, fp of the drugs was measured by the equilibrium dialysis method. For FK, the meanf,values(fSE) were 1-31+0*18per~ent(2.Opgml-~)and 1.93k0.18percent (5*Opgml-'). For CyA, the fp values were 4-85kO.36 per cent (l-Opgrnl-') and 5-75 kO.82 per cent (5.0 pg ml-I). The hydrophobicity parameter, l o p ' determined through the HPLC method was 0.386 for FK and 0.545 for CyA. Although FK was less hydrophobic than CyA, its protein binding was higher than CyA.