Tacrolimus + Phenytoin

Tacrolimus + Phenytoin

An isolated report describes an increase in serum phenytoin levels attributed to the use of tacrolimus. Phenytoin decreased tacrolimus levels in one case, and has been used to reduce tacrolimus levels after an overdose.

Clinical evidence

(a) Phenytoin levels
A kidney transplant patient taking phenytoin 500 and 600 mg on alternate days (and also taking azathioprine, bumetanide, digoxin, diltiazem, heparin, insulin and prednisone) had his immunosuppressant treatment changed from ciclosporin, to tacrolimus 14 to 16 mg daily.
About 7 weeks later he presented to hospital because of a fainting episode and his phenytoin levels were found to have risen from 18.4 to 36.2 micrograms/mL. The phenytoin was temporarily stopped until his serum levels had fallen, and he was then discharged on a reduced phenytoin dosage of 400 and 500 mg on alternate days with no further problems.1
The presumption is that the fainting episode was due to the raised serum phenytoin levels.
 

(b) Tacrolimus levels
In one kidney transplant patient taking phenytoin, tacrolimus 250 micrograms/kg daily was needed to give a blood level of 9 nanograms/mL. Three months later phenytoin was gradually stopped, with gradual tapering of the tacrolimus dose. The patient was eventually stabilised with a tacrolimus dose of 160 micrograms/kg daily giving a blood level of 11 nanograms/mL.2
Another report describes the use of an intravenous phenytoin infusion to treat acute tacrolimus overdoses in 2 patients, with the aim of enhancing tacrolimus metabolism.3

Mechanism
Tacrolimus is extensively metabolised by the cytochrome P450 isoenzyme CYP3A4, and phenytoin is a known inducer of this system. Phenytoin is therefore predicted to decrease tacrolimus levels. In the first case, it was suggested that tacrolimus might have inhibited the metabolism of phenytoin, although other factors may have had some part to play in the raised phenytoin levels.1
 

Importance and management
No interaction is established, but based on the known metabolism of these drugs it would be prudent to monitor tacrolimus levels in a patient given phenytoin. Similarly, based on the single case of phenytoin toxicity, it may also be advisable to monitor phenytoin levels.
1. Thompson PA, Mosley CA. Tacrolimus-phenytoin interaction. Ann Pharmacother (1996) 30, 544.

2. Moreno M, Latorre C, Manzanares C, Morales E, Herrero JC, Dominguez-Gil B, Carreño A, Cubas A, Delgado M, Andres A, Morales JM. Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc (1999) 31, 2252–3.
3. Karasu Z, Gurakar A, Carlson J, Pennington S, Kerwin B, Wright H, Nour B, Sebastian A. Acute tacrolimus overdose and treatment with phenytoin in liver transplant recipients. J Okla State Med Assoc (2001) 94, 121–3.