Distribution and Protein Binding of FK506, a Potent Immunosuppressive Macrolide Lactone, in Human Blood and Its Uptake by Erythrocytes

Abstract

The distribution of FK506 in the blood was estimated in-vitro. At a drug level of 5 ng mL-1, FK506 mainly distributed in erythrocytes (95-98%) in dog, monkey and human blood, and its distribution was affected by drug concentration, temperature, and haematocrit values. In erythrocytes most of FK506 was distributed in cytoplasmic components and was bound strongly to a protein having a molecular weight of 10-11 kDa. The molecular weight of this protein agrees with FK506-binding protein found in various cells. Greater than 98.8% of FK506 was bound to the plasma proteins in all species studied. FK506 bound to various plasma proteins such as lipoproteins, globulins, alpha 1-acid glycoprotein and albumin.

Intestinal thrombotic microangiopathy induced by FK506 in rats

“…It is difficult in this rat model to clarify that anemia is the risk factor of intestinal TMA induced by FK506, because of relatively small intraerythrocytic distribution of FK506 in rat. 33 In conclusion, intestinal TMA was induced by intraperitoneal injection of FK506 alone in rats and its severity was dependent on the whole blood levels of FK506. The intestinal TMA at recovery phase showed histological findings resembling GVHD.…”

“…The plasma level of FK506 is changed according to hematocrit, because 98% of FK506 in the blood distributes in erythrocytes. [31][32][33] Therefore, anemia presented by most patients with hematological disorders could be an aggravating factor on the toxic effect of FK506.…”

Higher intracerebral concentration of tacrolimus after intermittent than continuous administration to rats

“…Tacrolimus exists in the whole blood binding to the immunophilin (FK506 binding protein [FKBP]) or red blood cells. 20 Bolus injection of a greater dose of tacrolimus increases the unbound fraction of tacrolimus, which leads to a greater clearance ratio of the drug. Therefore, greater doses of tacrolimus are associated with decreased whole-blood concentration of AUC values.…”

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

“…30,34,35 The drug rapidly distributes from plasma into the red blood cells. The high affinity of tacrolimus for red blood cells may be due to the high intracellular content of FKBP.…”

“…The high affinity of tacrolimus for red blood cells may be due to the high intracellular content of FKBP. 35,36 Measurable concentrations of tacrolimus are present in the lungs, spleen, heart, kidney, pancreas, brain and liver. 27 Therefore, the volume of distribution (V d ) of tacrolimus in plasma and blood is large and variable, ranging from 0.85 to 65 l/kg.…”