Methadone Valproate

Therefore, plasma concentrations for drugs metabolized by these isoforms will be affected (see Chapter 10). Thus, the addition of phenytoin to an AED regimen can reduce their plasma levels by inducing their CYP3A4 metabolism for carbamazepine, felbamate, lamotrigine, oxcarbazepine, tiagabine, valproate, and zonisamide. Other drugs for which metabolism is induced by phenytoin include methadone, theophylline, warfarin, and oral contraceptives. On the other hand, plasma phenytoin levels are increased by carbamazepine, felbamate, cimetidine, warfarin, chloramphenicol, isoniazid, and disulfiram. Plasma phenytoin levels are decreased by rifampin, antacids, and valproate (free phenytoin levels remain the same). 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Two patients who had methadone withdrawal symptoms while taking phenjdoin 300 to 400 mg daily, and one of them later when taking car-bamazepine 600 mg daily, became free from withdrawal symptoms when they were given valproate instead. It was also found possible to virtually halve their daily methadone dosage. ... 

Not fully established, but all of these antiepileptics (except larnotrigine and valproate) are recognised enzyme-inducers that can increase the metabolism of other drugs by the liver, thereby hastening their loss from the body. In one study it was found that phenytoin increased the urinary excretion of the main metabolite of methadone. ... 

Information is limited but the interaction between methadone and these enzyme-inducing antiepileptics appears to be established and of clinical importance. Anticipate the need to increase the methadone dosage in patients taking carbamazepine, phenytoin or phenobarbital. It may be necessary to give the methadone twice daily to prevent withdrawal symptoms appearing towards the end of the day. It seems probable that primidone will interact similarly because it is metabolised to phenobarbital. Also be aware of the need to reduce the methadone dose if any enzyme-inducing antiepileptic is stopped. Valproate appears not to interact. 

Methadone levels can be reduced by carbamazepine, phenobarbital or phenytoin. Valproate appears not to interact. An isolated report describes lamotrigine-associated rash and blood dyscrasias, which may have been associated with methadone use. 

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