Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice.
OBJECTIVE
Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)-induced seizures in mice.


METHODS
Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone-AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue.


RESULTS
Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect.


CONCLUSIONS
Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.
Zarnowska
Iwona
I
Department of Pathophysiology, Medical University, Lublin, Poland.
Luszczki
Jarogniew J
JJ
Zarnowski
Tomasz
T
Buszewicz
Grzegorz
G
Madro
Roman
R
Czuczwar
Stanislaw J
SJ
Gasior
Maciej
M
D000096:Acetone / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D055592:Biophysical Phenomena / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D007118:Immunoassay; D008297:Male; D051379:Mice; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology
D000927:Anticonvulsants; D000096:Acetone