Pharmacokinetic interaction in rabbits between a new anticonvulsant, DL-3-hydroxy-3-ethyl-3-phenylpropionamide, and phenytoin.
The effect of phenytoin on the disposition of DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) has been studied in New Zealand white rabbits. Plasma HEPP levels decreased when the drug was administered with phenytoin. The area under the plasma concentration-time curve was reduced by 56.49% (from 43.23+/-7.0 to 18.81+/-2.03 microg h mL(-1)), the elimination half-life was also significantly (P<0.01) reduced (from 2.68+/-0.35 to 1.04+/-0.07 h) and the clearance was increased (from 0.35 to 0.81 L h(-1) kg(-1)). In-vitro protein binding to bovine serum albumin (BSA) and plasma was evaluated by equilibrium dialysis. Plasma protein binding was low (between 33.69 and 37.43% at concentrations ranging from 6.25 to 100 microg mL(-1)). The compound binds preferentially to albumin with an association constant (Ka) of 3.81 x 10(3) M(-1) at 37 degrees C. The results suggest a pharmacokinetic interaction between phenytoin and HEPP, probably on the drug-metabolizing enzyme system in the liver.
Instituto Nacional de Neurología y Neurocirugía, Departamento de Farmacia, Facultad de Química, UNAM, México, DF.
L
L
Medina
L
L
García
R
R
Pérez
A
A
Fernández
H
H
Jung
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D004347:Drug Interactions; D008297:Male; D010666:Phenylpropionates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010949:Plasma / Q000378:metabolism; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism
D000927:Anticonvulsants; D010666:Phenylpropionates; D012709:Serum Albumin; C067697:beta-hydroxy-beta-ethyl-phenylpropionamide; D010672:Phenytoin