Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human.
Carbapenem antibiotics cause pharmacokinetic interaction with valproic acid (VPA) in clinical pharmacotherapy. Here, we investigated the mechanism of interaction from the viewpoint of erythrocyte distribution of VPA in rats and humans. Imipenem or panipenem was administered intravenously and then VPA intravenously or into the intestinal lumen in rats. Both imipenem and panipenem significantly decreased plasma VPA levels. In contrast, these antibiotics did not affect, or rather increased, VPA levels in whole blood, and increased the erythrocyte distribution of VPA in vivo. In clinical, two patients receiving VPA were given imipenem intravenously, because of intractable infectious diseases. Imipenem lowered plasma VPA levels by approximately 40%-60% of original levels, and increased the erythrocyte distribution of VPA, as observed in rats. In conclusion, the pharmacokinetic interaction between VPA and carbapenem antibiotics, in which plasma VPA levels were markedly reduced, may partly be derived from the increased erythrocyte distribution of VPA.
Department of Pharmaceutics and Therapeutics, Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Kei
K
Omoda
Teruo
T
Murakami
Ryoko
R
Yumoto
Junya
J
Nagai
Yorinobu
Y
Maeda
Yoshie
Y
Kiribayashi
Mikihisa
M
Takano
D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015780:Carbapenems / Q000494:pharmacology*; D004347:Drug Interactions; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D015378:Imipenem / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013845:Thienamycins / Q000494:pharmacology; D013997:Time Factors; D014635:Valproic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D015780:Carbapenems; D013845:Thienamycins; D014635:Valproic Acid; D015378:Imipenem; C039536:panipenem