Time-dependent disposition of tacrolimus and its effect on endothelin-1 in liver allograft recipients.
OBJECTIVE
To characterize a time-dependent disposition of oral tacrolimus and its relationship with plasma endothelin-1 concentrations.


METHODS
Randomized, crossover study.


METHODS
Clinical research center of a university-affiliated hospital.


METHODS
Twelve stable liver transplant recipients.


METHODS
In the steady state, 23 blood samples were taken from each patient before and after tacrolimus administration over 24 hours.


RESULTS
Whole blood samples for tacrolimus and plasma endothelin-1 were analyzed by enzyme immunoassay. The relationship of their concentrations and their pharmacokinetic parameters between morning and evening doses were compared. The area under the curve (AUC) of tacrolimus in the morning dose was significantly larger than that in the evening dose (219 +/- 54 ng.hr/ml and 188 +/- 57 ng.hr/ml, respectively, p = 0.004). The mean time to peak concentration (Tmax) was significantly shorter for the morning dose than for the evening dose (1.6 +/- 0.7 hrs and 3.5 +/- 2.9 hrs, respectively, p = 0.01). The mean peak concentration (Cmax) was significantly higher in the morning dose than in the evening dose (32.2 +/- 9.1 ng/ml and 21.6 +/- 8.3 ng/ml, respectively, p = 0.008). However, the mean through concentration (Cmin) was not significantly different between doses. Endothelin-1 concentrations followed the same pattern as tacrolimus, with AUC and Cmax for the morning significantly higher than those for the evening dose of tacrolimus (AUC 13.8 +/- 3.7 pg.hr/ml, morning, and 11.0 +/- 3.5 pg.hr/ml, evening, p = 0.005; Cmax 2.4 +/- 1.1 pg/ml morning, and 1.5 +/- 0.6 pg/ml evening, p = 0.02). Tacrolimus levels did not correlate with endothelin-1 levels (r2 = 0.06, p = 0.001).


CONCLUSIONS
Tacrolimus disposition in liver transplant patients is determined by time of administration. Plasma endothelin-1 concentrations follow the same pattern as blood tacrolimus concentrations.
Min
D I
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Division of Clinical and Administrative Pharmacy, College of Pharmacy, University of Iowa, Iowa City 52242, USA.
Chen
H Y
HY
Lee
M K
MK
Ashton
K
K
Martin
M F
MF
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D014184:Transplantation, Homologous
D019332:Endothelin-1; D007166:Immunosuppressive Agents; D016559:Tacrolimus