P-glycoprotein-dependent Disposition Kinetics of Tacrolimus: Studies in Mdr1a Knockout Mice

Purpose: This study was performed to evaluate the involvement of P-glycoprotein in disposition kinetics of tacrolimus (FK506), a substrate of P-glycoprotein, in the body.

Methods: The blood and tissue concentrations of FK506 after i.v. or p.o. administration (2 mg/kg) to normal and mdr1a knockout mice were measured by competitive enzyme immunoassay.

Results: The blood concentrations in knockout mice were significantly higher than those in normal mice. The value of the total clearance (CLtot) for knockout mice (19.3 mL/min/kg) was about 1/3 of that for normal mice (55.8 mL/min/kg)(P < 0.001), although there was no significant difference in the distribution volume at the steady-state (Vd(ss)) (about 4.6 L/kg) between both types of mice. FK506 rapidly penetrated the blood-brain barrier and the brain concentration reached a maximum, which was about 10 times higher in knockout mice than in normal mice, 1 hr after administration. The brain concentration in normal mice thereafter decreased slowly, whereas in knockout mice, an extremely high concentration was maintained for 24 hr.

Conclusions: The pharmacokinetic behavior of FK506 in the tissue distribution is related with the function of P-glycoprotein encoded by the mdrla gene. The brain distribution of FK506 is dominated by the P-glycoprotein-mediated drug efflux and presumably also by the binding to FK-binding proteins (immunophilins) in the brain.