Zonisamide is rapidly and completely absorbed, reaching peak concentrations in 2 to 6 hours. It is about 70% metabolized by the liver, with reduction by CYP 3A4 accounting for about 50% and N-acetylation accounting for 20% of the metabolism. There are no active metabolites. Other drugs that induce or inhibit CYP 3A4 may increase or decrease the clearance of zonisamide but zonisamide does not alter the concentrations of other AEDs or induce its own metabolism.
Zonisamide has a long half-life, around 63 hours in an uninduced patient and around 27 to 38 hours in an induced patient. The half-life would be expected to be greater than 63 hours in a patient taking enzyme-inhibiting drugs. About 30% of a dose of zonisamide is excreted unchanged in the urine. Zonisamide is only about 40% protein-bound.44-46
The pharmacokinetics of zonisamide in patients with liver dysfunction have not been formally evaluated. Because the drug is about 70% metabolized by reduction and acetylation, however, it is anticipated that the metabolism of zonisamide would be reduced in these patients.
Drugs like zonisamide with long half-lives require longer intervals between dosage adjustments to achieve steady state. Rapid titration of zonisamide has resulted in an increase in CNS side effects. Because the half-life of zonisamide is likely to be even more prolonged in patients with liver dysfunction, there should be a longer interval between dosage adjustments. Patients should be carefully evaluated clinically.
The effect of GI disease on zonisamide is unknown.
Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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