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

• Published in: Clinical pharmacology and therapeutics 2001-01, Vol.69 (1), p.24-31
• Main Authors: Mancinelli, Laviero M., Frassetto, Lynda, Floren, Leslie C., Dressler, Dawna, Carrier, Steve, Bekersky, Ihor, Benet, Leslie Z., Christians, Uwe
• Format: Article
• Language: English
• Subjects: Adult; African Americans; African Continental Ancestry Group; Biological and medical sciences; Ethnic Groups; European Continental Ancestry Group; Female; Hispanic Americans; Humans; Immunomodulators; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Infusions, Intravenous; Male; Medical sciences; Pharmacology. Drug treatments; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2001.113183

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 μg/L) than in the white subjects (37.8 μg/L) and Latin American subjects (33.0 μg/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 μg/L · h, geometric mean) than in the white (293 μg/L · h) and Latin American subjects (239 μg/L · 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. Clinical Pharmacology & Therapeutics (2001) 69, 24–31; doi: 10.1067/mcp.2001.113183