Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports.
OBJECTIVE
The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods ofphenytoin.


METHODS
A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy.


RESULTS
About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days.


CONCLUSIONS
The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.
Wada
K
K
Department of Pharmacy, National Cardiovascular Center, Osaka, Japan. kwada@hsp.ncvc.go.jp
Takada
M
M
Ueda
T
T
Ochi
H
H
Kotake
T
T
Morishita
H
H
Hanatani
A
A
Nakatani
T
T
D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007564:Japan; D010672:Phenytoin / Q000008:administration & dosage / Q000494:pharmacology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D007166:Immunosuppressive Agents; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus