Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits.
OBJECTIVE
We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits.


METHODS
Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM.


RESULTS
The plamsa total clearance of VPA was significantly increased to about 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P < 0.05). The values of the area under the plasma concentration-time curve (AUC) of 2-en-VPA, a product of beta-oxidation, and VPA-glucuronide (VPA-G) were significantly decreased to about 55% and 78% of the control, respectively (P < 0.05). The cumulative urinary excretions of VPA in the control and MEPM-treated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P < 0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchanged by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control.


CONCLUSIONS
The increase of the total clearance of VPA caused by MEPM appears to be a consequence of increased renal clearance of VPA-G, as well as suppression of VPA-G hydrolysis in the liver.
Yokogawa
K
K
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Japan.
Iwashita
S
S
Kubota
A
A
Sasaki
Y
Y
Ishizaki
J
J
Kawahara
M
M
Matsushita
R
R
Kimura
K
K
Ichimura
F
F
Miyamoto
K
K
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D008297:Male; D000077731:Meropenem; D011817:Rabbits; D013845:Thienamycins / Q000494:pharmacology*; D014018:Tissue Distribution; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000927:Anticonvulsants; D020719:Glucuronides; D013845:Thienamycins; D014635:Valproic Acid; D000077731:Meropenem