Severe elevations of FK506 blood concentration due to diarrhea in renal transplant recipients.
BACKGROUND
The rate of metabolism in the intestine of oral administered FK506 decreases as FK506 passes on to the lower intestine. In transplant recipients with diarrhea given oral FK506, the main areas for absorption of FK506 shift to the lower intestine, where the ability to metabolize FK506 is weaker. Therefore it is considered likely that when FK506 is administered to recipients with diarrhea, the blood concentration of FK506 will be higher.


METHODS
Twenty recipients experiencing episodes of diarrhea were investigated to determine the trough level of FK506 and the time required for the FK506 trough level to return to the level that obtained before diarrhea. AUC0-4h and Cmax of FK506 were investigated in eight recipients. In cases with severe diarrhea, the daily fluctuations of FK506 blood concentration were also investigated.


RESULTS
The FK506 trough level (p < 0.0001), AUC (p = 0.0173), and Cmax (p = 0.0173) were found to be significantly higher during episodes of diarrhea. In almost all cases, it took between 2 and 4 wk for the elevated FK506 trough level to return to its previous level following a bout of diarrhea. In the daily fluctuations of FK506 concentration, Tmax was prolonged. In some cases, the concentration was highest just before administration of FK506, when it should have been at trough level.


CONCLUSIONS
Diarrhea caused significant elevations of trough level, AUC0-4h and Cmax of FK506, and the prolongation of Tmax in renal transplant recipients administered FK506.
Sato
Koichiro
K
Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, Sendai, Japan. ksato@mtd.biglobe.ne.jp
Amada
Noritoshi
N
Sato
Takaomi
T
Miura
Shunji
S
Ohashi
Yoichi
Y
Sekiguchi
Satoshi
S
Satomi
Susumu
S
Okazaki
Hajime
H
D000284:Administration, Oral; D019540:Area Under Curve; D002940:Circadian Rhythm; D003404:Creatinine / Q000097:blood; D003967:Diarrhea / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000502:physiology; D016030:Kidney Transplantation / Q000502:physiology; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics
D007166:Immunosuppressive Agents; D003404:Creatinine; D016559:Tacrolimus