The study is being done to understand why some patients with epilepsy (disease of recurrence
of seizures) do not respond very well to drug treatment with anticonvulsants.
Despite the availability of many anticonvulsants, about 30% of patients with epilepsy are
resistant to them. The cause of the resistance is not clear, but one of the reasons could be
an increased amount of proteins in the cells of the body called transporter proteins.
Transporter proteins are a group of proteins that help to defend the body against toxins,
including drugs, by pumping them out of the cells. Studies have shown that the number of
transporter proteins is higher in the parts of the brain that trigger seizures when compared
to other parts of the brain.
Studies in animals have shown that taking an anticonvulsant with an inhibitor (meaning "to
stop" or "to reduce") of a transporter protein can increase the concentration of that
anticonvulsant inside the brain cells. The main purpose of the study is to determine if
taking an anticonvulsant and a transporter protein inhibitor will change the brain
concentration of the anticonvulsant.
In this study, a single dose of phenytoin (Dilantin® is a brand name anticonvulsant which
has phenytoin as its active ingredient), a commonly used anticonvulsant, will be given once
by itself, and then will be given a separate time with a single (i.e. one time only) dose of
probenecid. Probenecid, a medicine used commonly to treat gout (a disease of increased uric
acid), is known to be an inhibitor of transporter proteins. The study will use
electroencephalogram or EEG (recording of brain wave activities) to determine if the EEG
pattern when probenecid is given, will be different from the EEG pattern when phenytoin is
given alone. This will suggest that probenecid has affected the brain concentration of
About 30% of patients with epilepsy are refractory to medical treatment (pharmacoresistant
epilepsy). The cause of which is multifactorial. Multidrug resistance (MDR) causes
decreased uptake of medicines in tissues. MDR occurs because of overexpression of a family
of transporter proteins that act as a physiological defense mechanism that pumps toxins out
of cells. Two groups of transporters, P-glycoprotein (PGP) and multidrug
resistance-associated proteins (MRP), are important gatekeepers in the blood brain barrier.
PGP and MRP are overexpressed in the brain tissue of pharmacoresistant patients with partial
epilepsy and many antiepileptic drugs (AEDs) are substrates for PGP, MRP or both.
It is logical to try to apply these observations to clinical practice. We hope that through
co-administration of an inhibitor of transporter proteins, we can increase the CNS
concentrations of AEDs, and subsequently improve seizure control. However, before this, it
is critical to demonstrate that a transporter protein inhibitor can increase the
concentration of AEDs in human brain.
Probenecid is an MRP inhibitor while phenytoin is an MRP substrate. Evaluating whether
probenecid can increase the CNS concentration of PHT can potentially be achieved
noninvasively by using pharmaco-EEG.
We plan to estimate the effect of probenecid (a transporter protein inhibitor) on the
quantitative EEG recordings when it is administered to patients with pharmacoresistant
epilepsy and in normal healthy volunteers.
We plan to recruit two groups of 10 subjects each, normal volunteers and patients with
pharmacoresistant epilepsy. They will undergo two treatment regimens; EEG recording after
administration of intravenous phenytoin only and again after pre-dosing them with
- Men with pharmacoresistant partial epilepsy defined as failure of two or more AEDs at
a reasonable therapeutic dose
- Patient is able to understand and sign a consent form and able to keep a seizure
- Patient is older than 18 years of age
- Patient is otherwise healthy by laboratory and physical examination
- Patient is currently taking phenytoin
- Patient has a history of an adverse reaction to phenytoin
- Patient has a history of gout disease, peptic ulcer disease, blood dyscrasias, or
uric acid kidney stones
- Patient has an allergy to sulfa drugs or probenecid
- Patient has been exposed to probenecid or another known transporter inhibitor
(verapamil, progesterone, etc) in the three months prior to enrollment
- Patient has a history of renal impairment (creatinine clearance < 50 ml/min)
- Patient has a history of diabetes and is taking oral sulfonylurea agents