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Molecular Diagnostics and Genetics |
Departments of1
Clinical Pharmacology and2
Clinical Chemistry, Georg-August University, Goettingen, Germany.
3 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
4 Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
aAddress correspondence to this author at: Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. Fax 49-941-5992-36727; e-mail wojnowski{at}uni-mainz.de.
Background: Tacrolimus is metabolized predominantly to 13-O-demethyltacrolimus in the liver and intestine by cytochrome P450 3A (CYP3A). Patients with high concentrations of CYP3A5, a CYP3A isoenzyme polymorphically produced in these organs, require higher doses of tacrolimus, but the exact mechanism of this association is unknown.
Methods: cDNA-expressed CYP3A enzymes and a bank of human liver microsomes with known CYP3A4 and CYP3A5 content were used to investigate the contribution of CYP3A5 to the metabolism of tacrolimus to 13-O-demethyltacrolimus as quantified by liquid chromatography–tandem mass spectrometry.
Results: Demethylation of tacrolimus to 13-O-demethyltacrolimus was the predominant clearance reaction. Calculated Km and Vmax values for CYP3A4, CYP3A5, and CYP3A7 cDNA-expressed microsomes were 1.5 µmol/L and 0.72 pmol · (pmol P450)–1 · min–1, 1.4 µmol/L and 1.1 pmol · (pmol P450)–1 · min–1, and 6 µmol/L and 0.084 pmol · (pmol P450)–1 · min–1, respectively. Recombinant CYP3A5 metabolized tacrolimus with a catalytic efficiency (Vmax/Km) that was 64% higher than that of CYP3A4. The contribution of CYP3A5 to 13-O-demethylation of tacrolimus in human liver microsomes varied from 1.5% to 40% (median, 18.8%). There was an inverse association between the contribution of CYP3A5 to 13-O-demethylation and the amount of 3A4 protein (r = 0.90; P <0.0001). Mean 13-O-demethylation clearances in CYP3A5 high and low expressers, estimated by the parallel-tube liver model, were 8.6 and 3.57 mL · min–1 · (kg of body weight)–1, respectively (P = 0.0088).
Conclusions: CYP3A5 affects metabolism of tacrolimus, thus explaining the association between CYP3A5 genotype and tacrolimus dosage. The importance of CYP3A5 status for tacrolimus clearance is also dependent on the concomitant CYP3A4 activity.
The following articles in journals at HighWire Press have cited this article:
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  K. Hosohata, S. Masuda, T. Katsura, Y. Takada, T. Kaido, Y. Ogura, F. Oike, H. Egawa, S. Uemoto, and K.-i. Inui Impact of Intestinal CYP2C19 Genotypes on the Interaction between Tacrolimus and Omeprazole, but Not Lansoprazole, in Adult Living-Donor Liver Transplant Patients Drug Metab. Dispos., April 1, 2009; 37(4): 821 - 826. [Abstract] [Full Text] [PDF]
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