The antiepileptic drugs find their major application in treatment of various kinds of epilepsy, although some of them are also used for other conditions, such as pain management.
The drugs used as antiepileptics are a disparate group,and their interactions need to be considered individually. Carbamazepine and phenytoin have established ranges of therapeutic plasma levels and these are typically fairly narrow. Modest changes in plasma levels may therefore be clinically important.
Carbamazepine is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 to active metabolite, carbamazepine-10,11-epoxide, which is then further metabolised. Concurrent use of CYP3A4 inhibitors or inducers may therefore lead to toxicity or reduced efficacy. However,importantly, carbamazepine also induces CYP3A4 and so induces its own metabolism (autoinduction). Because of this,it is important that drug interaction studies are multiple-dose and carried out at steady state. Auto-induction also means that moderate inducers of CYP3A4 may have less of an effect on steady-state carbamazepine levels than expected. Oxcarbazepine is a derivative of carbamazepine,but has a lesser effect on CYP3A4. However,both carbamazepine and oxcarbazepine can act as inhibitors of CYP2C19, see Phenytoin + Carbamazepine interaction.
Phenobarbital is an inducer of a wide range of cytochrome P450 isoenzymes, and may increase metabolism of a variety of drugs. It may,itself, also be affected by some enzyme inducers or inhibitors, although these interactions are less established.
Phenytoin is extensively metabolised by hydroxylation,principally by CYP2C9, although CYP2C19 also plays a role. These isoenzymes show genetic polymorphism’,, and CYP2C19 may assume a greater role in individuals who have a poor metaboliser phenotype of CYP2C9. The concurrent use of inhibitors of CYP2C9,and sometimes also CYP2C19, can lead to phenytoin toxicity. In addition,phenytoin metabolism is saturable (it shows non-linear pharmacokinetics), and therefore small changes in metabolism or phenytoin dose can result in marked changes in plasma levels. Moreover,phenytoin is highly protein bound, and drugs that alter its protein binding may alter its levels. Although protein binding interactions are usually not clinically relevant (unless metabolism is also inhibited,see ‘Phenytoin + Valproate), they can be important in interpreting drug levels.
Valproate is a generic name that is applied in this section to cover valproic acid and its salts and esters. Valproate undergoes glucuronidation and :7.8pt; font-weight:normal; color:#000000″>βoxidation,and possibly also some metabolism via CYP2C isoenzymes. It can therefore undergo drug interactions via a variety of mechanisms. It acts as an inhibitor of glucuronidation and so may affect other drugs that undergo glucuronidation. Valproate also has non-linear pharmacokinetics due to saturation of plasma protein binding,and so may interact with drugs that alter its protein binding. However,note that, although protein binding interactions are usually not clinically relevant unless metabolism is also inhibited, they can be important in interpreting drug levels.
Of newer antiepileptics, both felbamate and topiramate are weak inducers of CYP3A4. They may also inhibit CYP2C19. They are also partially metabolised by cytochrome P450 isoenzyme system, so may have their metabolism altered by other drugs such as older enzyme-inducing antiepileptics.
Gabapentin, lamotrigine, levetiracetam, tiagabine, vigabatrin, and zonisamide do not appear to act as inhibitors or inducers of cytochrome P450 isoenzymes, and so appear to cause less drug interactions than older antiepileptics. Moreover, gabapentin, levetiracetam, and vigabatrin do not appear to be metabolised by cytochrome P450 system, so appear to be little affected by drug interactions that result from this mechanism. Tiagabine and zonisamide are metabolised by cytochrome P450 system, so may have their metabolism altered by other drugs such as older enzyme-inducing antiepileptics. Lamotrigine is metabolised by glucuronidation,and may be affected by inhibitors (e.g. valproate) or inducers (e.g. the older enzyme-inducing antiepileptics) of this process. Lamotrigine may also act as an inducer of glucuronidation.