title: Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit.
abstract: OBJECTIVE
  The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.
  
  
  METHODS
  Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.
  
  
  RESULTS
  Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h(-1) at day 7; 17 ± 9.1 l h(-1) at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min(-1) at day 7 vs. 730 ± 344 ml min(-1) at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min(-1) for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.
  
  
  CONCLUSIONS
  The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.
authors.affiliation: Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hylke
authors.initials: H
authors.lastname: de Jonge
authors.affiliation: Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanhove
authors.affiliation: Laboratory of Nephrology, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Henriëtte
authors.initials: H
authors.lastname: de Loor
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium.
authors.forename: Kristin
authors.initials: K
authors.lastname: Verbeke
authors.affiliation: Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
mesh_terms: D019540:Area Under Curve; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006400:Hematocrit; D006801:Humans; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D016559:Tacrolimus
keywords: CYP3A4; CYP3A5; CYP3A5*1; cyclosporine; kidney transplantation; tacrolimus