The disposition of C-14-labeled tacrolimus after intravenous and oral administration in healthy human subjects

Tacrolimus is a macrolide lactone with potent immunosuppressive properties. It has been shown in clinical studies to prevent allograft rejection. The pharmacokinetics of tacrolimus in healthy subjects and transplant patients has been described in earlier studies using immunoassay methods; however, d etailed information on the absorption, distribution, metabolism, and excret ion of tacrolimus using a radiolabeled drug is lacking. The objective of th e present study was to characterize the disposition of tacrolimus after sin gle i.v. (0.01 mg/kg) and oral (0.05 mg/kg) administration of C-14-labeled drug in six healthy subjects. Tacrolimus was absorbed rapidly after oral do sing with a mean C-max and T-max of 42 ng/ml and 1 h, respectively. The ora l bioavailability was about 20%. After i.v. and oral dosing, most of the ad ministered dose was recovered in feces, suggesting that bile is the princip al route of elimination. Urinary excretion accounted for less than 3% of to tal administered dose. In systemic circulation, unchanged parent compound a ccounted for nearly all the radioactivity; however, less than 0.5% of uncha nged drug was detectable in feces and urine. The excretion of the metabolit es was formation-rate-limited. The mean total body clearance at 37.5 ml/min was equivalent to about 3% of the liver blood flow, Renal clearance was le ss than 1% of the total body clearance. The mean elimination half-life was 44 h.