The pharmacokinetics and metabolic disposition of tacrolimus: A comparisonacross ethnic groups

Objective: Our objective was to compare the intravenous and oral pharmacoki netics 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 rec eived intravenous and oral tacrolimus in an open-label, two-period, paralle l group study. All of the subjects received intravenous tacrolimus (0.015 m g/kg) as a constant infusion over 4 hours and oral tacrolimus capsules (5 m g) as single doses in randomized order. Concentrations of tacrolimus and it s metabolites were measured in whole blood with the use of a validated HPLC -mass spectrometry assay. Results: There were no significant differences in pharmacokinetic parameter s among the three study groups after intravenous administration of the drug s. After oral administration, the tacrolimus maximum concentration was sign ificantly lower (P < .01) in the African American subjects (20.8 <mu>g/L) t han in the white subjects (37.8 mug/L) and Latin American subjects (33.0 mu g/L). Absolute bioavailability was significantly lower (P = .01) in the Afr ican American subjects (11.9%) and in the Latin American subjects (14.4%) t han 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 mug/L.h, geometric mean) than in the white (293 mug/L.h) and Latin Ame rican subjects (239 mug/L.h, differences not statistically significant). Ma ximum 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 t he white and Latin American subjects. Conclusions: Significant differences in tacrolimus pharmacokinetics exist a mong the three different ethnic groups. Our results indicate that this may result from differences in intestinal CYP3A or P-glycoprotein activities.