Tiagabine enzymes

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Tiagabine is 90-100% bioavailable, has linear kinetics, and is highly protein-bound. The half-life is 5-8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). Hepatic impairment causes a slight decrease in clearance (and may necessitate a lower dose), but the drug does not cause inhibition or induction of hepatic... 

Clearance of tiagabine may be reduced and thus plasma levels increased if taken with a non-enzyme inducing antiepileptic drug (e.g., valproate, gabapentin, lamotrigine), so tiagabine dose may need to be reduced... 

Clearance of tiagabine is increased if taken with an enzyme-inducing antiepileptic drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone) and thus plasma levels are reduced however, no dose adjustments are necessary for treatment ot epilepsy as the dosing recommendations for epilepsy are based on adjunctive treatment with an enzyme-inducing antiepileptic drug... 

Both patients were taking a non-enzyme-inducing agent (valproate and lamotrigine respectively), which probably resulted in higher serum tiagabine concentrations than those seen in enzyme-induced patients. 

The most important interactions of tiagabine involve induction of its metabolism by enzyme-inducing anticonvulsants (30). This results in larger tiagabine dosage requirements compared with patients taking monotherapy or valproic acid co-medication. 

Vigabatrin acts by blocking GABA-T, the enzyme responsible for the breakdown of GABA (Fig. 6.5) tiagabine acts by inhibiting the reuptake of the neurotransmitter. 

So EL, Wolff D> Graves NM, Leppik IE, Cascino GD, Pixton GC, et al. Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepdepsy drugs. Epilepsy Res 1995 22 221-6. 

Drug Interactions. Enzyme inducers, such as carbamazepine and phenytoin, increase tiagabine clearance and decrease the half-life. Food decreases the rate but not the extent of absorption. Tiagabine is displaced from protein by naproxen, salicylates, and valproate. However, tiagabine does not displace phenytoin, valproic acid, amitrypty-line, tolbutamide, or warfarin. ... 

Tiagabine is rapidly absorbed after oral administration, extensively bound to serum or plasma proteins, and metabolized mainly in the liver, predominantly by CYP3A. Its half-life of about 8 hours is shortened by 2 to 3 hours when coadministered with hepatic enzyme-inducing drugs such as phenobarbital, phenytoin, or carbamazepine. 

Because of its inducing effect on hepatic enzymes, phenobarbitai has many drug interactions, decreasing plasma levels of CBZ, valproate, lamotrigine, tiagabine, zonisamide, warfarin, theophylline, cimetidine, and those of other CYP3A4 substrates. Serum concentrations of phenobarbitai are increased by valproate. 

Tiagabine piasma ieveis are reduced by enzyme-inducing antiepileptics (carbamazepine, phenytoin, phenobarbital and primi-... 

---