Pharmacodynamic and pharmacokinetic interaction studies of loreclezole with felbamate, lamotrigine, topiramate, and oxcarbazepine in the mouse maximal electroshock seizure model.
OBJECTIVE
The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis.


METHODS
Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established.


RESULTS
With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task.


CONCLUSIONS
LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.
Luszczki
Jarogniew J
JJ
Department of Pathophysiology, Skubiszewski Medical University of Lublin, Lublin, Poland.
Ratnaraj
Neville
N
Patsalos
Philip N
PN
Czuczwar
Stanislaw J
SJ
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004597:Electroshock; D000078328:Felbamate; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007696:Kindling, Neurologic / Q000187:drug effects / Q000378:metabolism; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000078330:Oxcarbazepine; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D014230:Triazoles; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; C066440:loreclezole; D000077213:Lamotrigine; D000078330:Oxcarbazepine; D000078328:Felbamate