The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups

Abstract

Objective: Our objective was to compare the intravenous and oral pharmacokinetics of tacrolimus among subjects of three different ethnic backgrounds, African American, white, and Latin American.

Methods: Ten African American, 12 white, and 12 Latin American subjects received intravenous and oral tacrolimus in an open-label, two-period, parallel group study. All of the subjects received intravenous tacrolimus (0.015 mg/kg) as a constant infusion over 4 hours and oral tacrolimus capsules (5 mg) as single doses in randomized order. Concentrations of tacrolimus and its metabolites were measured in whole blood with the use of a validated HPLC-mass spectrometry assay.

Results: There were no significant differences in pharmacokinetic parameters among the three study groups after intravenous administration of the drugs. After oral administration, the tacrolimus maximum concentration was significantly lower (P < .01) in the African American subjects (20.8 microg/L) than in the white subjects (37.8 microg/L) and Latin American subjects (33.0 microg/L). Absolute bioavailability was significantly lower (P = .01) in the African American subjects (11.9%) and in the Latin American subjects (14.4%) than in the white subjects (18.8%). After the oral dose, the area under the plasma concentration-time curve was lower in the African American subjects (179 microg/L x h, geometric mean) than in the white (293 microg/L x h) and Latin American subjects (239 microg/L x h, differences not statistically significant). Maximum concentration (P < .02) and area under the plasma concentration-time curve (not statistically significant) of the main tacrolimus metabolite 13-O-desmethyl tacrolimus was lower in the African American subjects than in the white and Latin American subjects.

Conclusions: Significant differences in tacrolimus pharmacokinetics exist among the three different ethnic groups. Our results indicate that this may result from differences in intestinal CYP3A or P-glycoprotein activities.