Hylke de Jonge1, Thomas Vanhove1, Henriëtte de Loor2, Kristin Verbeke3, Dirk R J Kuypers1. 1. Departments of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. 2. Laboratory of Nephrology, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium. 3. Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospitals Leuven, Leuven, Belgium.
Abstract
AIMS: 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.
AIMS: 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: T Aoyama; S Yamano; D J Waxman; D P Lapenson; U A Meyer; V Fischer; R Tyndale; T Inaba; W Kalow; H V Gelboin Journal: J Biol Chem Date: 1989-06-25 Impact factor: 5.157
Authors: J S McCune; R L Hawke; E L LeCluyse; H H Gillenwater; G Hamilton; J Ritchie; C Lindley Journal: Clin Pharmacol Ther Date: 2000-10 Impact factor: 6.875
Authors: Elly M van Duijnhoven; Johannes M M Boots; Maarten H L Christiaans; Leo M L Stolk; Nasrullah A Undre; Johannes P van Hooff Journal: Transpl Int Date: 2003-06-24 Impact factor: 3.782
Authors: Frank Stifft; Franciscus Vandermeer; Cees Neef; Sander van Kuijk; Maarten H L Christiaans Journal: Eur J Clin Pharmacol Date: 2020-02-04 Impact factor: 2.953
Authors: David R Darley; Lilibeth Carlos; Stefanie Hennig; Zhixin Liu; Richard Day; Allan R Glanville Journal: Eur J Clin Pharmacol Date: 2019-03-12 Impact factor: 2.953