Zonisamide Phenobarbital

Carbamazepine, phenytoin, phenobarbital, valproate, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide... 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Phenobarbital Phenytoin (Dilantin) Tiagabine (Gabitril) Topiramate (Topamax) Valproic Acid (Depakene, Depakote) Zonisamide (Zonegran)... 

Partial seizures Carbamazepine Phenytoin Lamotrigine Valproic acid Oxcarbazepine Gabapentin Topiramate Levetiracetam Zonisamide Tiagabine Primidone, phenobarbital Felbamate... 

Enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and primidone) may decrease plasma levels of zonisamide... 

Chronic treatment with phenobarbital, phenytoin, and carbamazepine is associated with reduced serum folate concentrations. Although megaloblastic anemia is rare, macrocytic changes in red cells are common in these patients. The fact that serum folate is not reduced by valproate and zonisamide, which do not induce liver enzymes, is consistent with the hypothesis that enzyme induction plays a role in the pathogenesis of folate deficiency (99). 

Phenobarbital Phenytoin Primidone Felbamate Lamotrigine Tiagabide Topiramate Valproate Zonisamide Clobazam Clonazepam Diazepam usually compensated by the effect of the added drug risk of toxicity when interfering drug is discontinued drug... 

The traditional treatment of tonic-clonic seizures is phenytoin or phenobarbital however, the use of carbamazepine and valproic acid is increasing because these AEDs have a lower incidence of side effects and equal efficacy. Valproic acid generally is considered the drug of first choice for atonic seizures and for juvenile myoclonic epilepsy. Lamotrigine and perhaps topiramate and zonisamide may be alternative agents for these seizure types. 

Sample preparation 500 pL Serum + 600 pL allobarbital in 75 mM pH 6.8 phosphate buffer, add 200 units p-glucuronidase, heat at 37°for 30 min, add 1 mL of this solution to an Extrelut-1 SPE cartridge, let stand for 10 min, elute with 2.5 mL MTBE. Evaporate the eluate to dryness under a stream of nitrogen, reconstitute the residue in 50 pL MeOH water 50 50, inject a 10 pL aliquot onto columns A and B in series and elute with mobile phase A. After 12 min elute colunm A with mobile phase B, continue to elute column B with mobile phase A. Carbeunazepine diol, carbamazepine epoxide, phen3d in, and carbamazepine elute from colunm A and the enantiomers of 5-(p-hydroxyphenyl)-5-phenylhydantoin and mephobeu-bital, phenobarbital, zonisamide, and allobarbital elute from colunm B. Re-equilibrate colunms A and B with mobile phase A for 5 min before the next injection. 

Extracted metabolites, carbamazepine, carbamazepine diol, carbamazepine epoxide, 5-(p-hydroxyphenyl)-5-phenylhydantoin, mephobarbital, phenobarbital, zonisamide... 

PHARMACOKINETICS Zonisamide is almost completely absorbed after oral administration, has a long tj, ( 63 hours), and is -40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetaboUzed zonisamide and a glucuronide of the CYP3A4 metabolite, sulfamoylacetyl phenol. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Zonisamide has Uftle effect on the plasma concentrations of other antiseizure drugs. 

After each depolarization, voltage-dependent sodium channels adopt an inactive state and remain refractory to reopening for a period of time. While those channels are unable to open, rapid repetitive firing is diminished, and spread of electrical seizure activity to adjacent brain regions is suppressed (14). Stabilization and prolongation of this inactive state appears to be the primary mechanism of action of phenytoin, carbamazepine, and lamotrigine and may be instrumental in the antiseizure actions of phenobarbital, oxcarbazepine, valproate, topiramate, and zonisamide (Fig. 20.2). 

Primidone use Is associated with decreases In CBZ, lamotrigine, valproate, tiagabine, and zonisamide serum levels. Primidone levels are increased by nicotinamide and Isonlazid. Hydantoins increase the plasma concentrations of primidone, phenobarbital, and PEMA. CBZ Increases levels of phenobarbital derived from primidone. Primidone levels are decreased by succinimides, CBZ, and acetazolamide. 

Schentag JJ, Gengo FM, Wilton JH, Sedman AJ, Grasela TH, Brockbrader HN. Influence of phenobarbital, cimetidine, and renal disease on zonisamide kinetics. Pham Res (1987) 4 (Sup-... 

Phenobarbital, phenytoin and carbamazepine can cause a small to moderate reduction in the serum levels of zonisamide, while lamotrigine may increase zonisamide levels. Clonazepam and valproate have little or no effect. Zonisamide shows variable effects (a modest decrease, an increase, or no effect) on carbamazepine serum levels, but has no important effect on lamotrigine, phenobarbital, primidone or valproate levels. Most studies also suggest that zonisamide has no effect on phenytoin levels, but two showed a modest increase. 

In one study the ratio of plasma level to dose of zonisamide was 29% lower in 11 patients also taking phenobarbital than in 28 patients taking zonisamide alone, suggesting that phenobarbital reduces zonisamide levels. Similarly, another study in healthy subjects found that pretreatment with phenobarbital increased the clearance of a single dose of zonisamide by about twofold. A further study found no changes in the serum levels of phenobarbital or primidone in 34 and 13 patients, respectively, who were also given zonisamide. ... 

Uncertain. It seems possible that phenobarbital, phenytoin and car-bamazepine can induce the metabolism of zonisamide thereby reducing its serum levels. The plasma protein binding of zonisamide is unaffected by other antiepileptics (phenobarbital, phenytoin, carbamazepine, valproate). ... 

None of these studies reported any major problems during concurrent use of zonisamide and these other antiepileptic drugs. Zonisamide serum levels are lower with phenobarbital, phenytoin and carbamazepine, and there is the possibility of carbamazepine or phenytoin level changes, so it would be prudent to monitor patients taking any of these combinations. 

---