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.
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.
Authors: R Venkataramanan; A Swaminathan; T Prasad; A Jain; S Zuckerman; V Warty; J McMichael; J Lever; G Burckart; T Starzl Journal: Clin Pharmacokinet Date: 1995-12 Impact factor: 6.447
Authors: P Borst; A H Schinkel; J J Smit; E Wagenaar; L Van Deemter; A J Smith; E W Eijdems; F Baas; G J Zaman Journal: Pharmacol Ther Date: 1993-11 Impact factor: 12.310
Authors: M R Bull; J A Spicer; K M Huttunen; W A Denny; A Ciccone; K A Browne; J A Trapani; N A Helsby Journal: Eur J Drug Metab Pharmacokinet Date: 2014-08-26 Impact factor: 2.441
Authors: Songmao Zheng; Thomas R Easterling; Jason G Umans; Menachem Miodovnik; Justina C Calamia; Kenneth E Thummel; Danny D Shen; Connie L Davis; Mary F Hebert Journal: Ther Drug Monit Date: 2012-12 Impact factor: 3.681