Phenytoin Interactions

Phenytoin induces hepatic CYP3A4 and CYP24A1, accelerating conversion of 25-hydroxyvitamin D to inactive metabolites and lowering circulating 25(OH)D, which over time produces secondary hyperparathyroidism, reduced calcium absorption, and a measurably increased risk of osteomalacia and fractures.

Phenytoin lowers serum and red-cell folate through enzyme induction and impaired absorption of polyglutamate folates, but high-dose folate supplementation in turn accelerates phenytoin metabolism and can drop drug levels enough to cause seizure breakthrough.

St. John's Wort is a potent inducer of CYP3A4, CYP2C9, CYP2C19, and P-glycoprotein via activation of the pregnane X receptor. Because phenytoin is heavily metabolized by CYP2C9 and CYP2C19, concurrent St. John's Wort can lower phenytoin plasma concentrations into the subtherapeutic range, increasing the risk of breakthrough seizures.

Ginkgo biloba induces CYP2C19, the primary enzyme responsible for phenytoin metabolism. A published case report described a fatal breakthrough seizure in a patient on phenytoin and valproate whose autopsy revealed subtherapeutic anticonvulsant levels and self-administration of ginkgo biloba. Ginkgo also has independent pro-convulsant potential at high doses and through ginkgotoxin contamination.

Star fruit (Averrhoa carambola) contains caramboxin, a neurotoxin that activates excitatory neuroreceptors and inhibits GABA, and high oxalate content that causes acute kidney injury. In patients with renal impairment, star fruit ingestion has triggered refractory status epilepticus, directly antagonizing phenytoin's seizure-prevention purpose.

Phenytoin reduces calcium absorption by accelerating vitamin D catabolism and by directly inhibiting active transcellular calcium transport in intestinal enterocytes; separately, calcium-containing antacids and supplements can chelate phenytoin in the gut and lower its absorption when taken simultaneously.