Note that tricyclics also lower convulsive threshold
The serum phenytoin levels of 2 patients rose over a 3-month period when they were given imipramine 75mg daily. One of them had an increase in phenytoin levels from about 7.6 to 15 micrograms/mL and developed mild toxicity (drowsiness and uncoordination). These signs disappeared and phenytoin serum levels of both patients fell when imipramine was withdrawn. One of them was also taking nitrazepam and clonazepam, and other sodium valproate and carbamazepine, but were stable on these combinations before addition of imipramine (See reference number 1).
Other studies have shown that nortriptyline 75 mg daily had an insignificant effect on serum phenytoin levels of 5 patients,(See reference number 2) and that amitriptyline had no effect on elimination of phenytoin in 3 subjects (See reference number 3)
A report describes 2 patients who had low serum desipramine levels,despite taking standard dosages, while they were also taking phenytoin (See reference number 4).
One suggestion is that imipramine inhibits metabolism of phenytoin by liver, which results in its accumulation in body. In vitro study(See reference number 5) has shown that tricyclics can inhibit cytochrome P450 isoenzyme CYP2C19, but this isoenzyme usually has only a minor role in phenytoin metabolism (see Antiepileptics,). The reduced desipramine levels may be a result of enzyme induction by phenytoin.
The documentation is very limited indeed and none of these interactions is adequately established. The results of in vitro study suggest that interaction may only assume importance in those who are deficient in CYP2C9, enzyme usually responsible for phenytoin metabolism (See reference number 5). The tricyclic antidepressants as a group lower seizure threshold,(See reference number 6) which suggests extra care should be taken if deciding to use them in epileptic patients. If concurrent use is undertaken effects should be very well monitored.
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