Carbapenem antibiotics inhibit valproic acid transport in Caco-2 cell monolayers

The concomitant use of carbapenem antibiotics with valproic acid has been prohibited because carbapenems induced a decrease in plasma concentration of valproic acid in epileptic patients during valproic acid therapy. Our previous in vivo study in rats proposed that inhibition by carbapenem of the in...

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Bibliographic Details
Published in:	International journal of pharmaceutics Vol. 233; no. 1; pp. 253 - 256
Main Authors:	Torii, Mayumi, Takiguchi, Yoshiharu, Izumi, Miyako, Fukushima, Tokuya, Yokota, Masayuki
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier B.V 21-02-2002 Elsevier
Subjects:	Anticonvulsants - antagonists & inhibitors Anticonvulsants - pharmacokinetics Biological and medical sciences Biological Transport - drug effects Caco-2 cell monolayer Caco-2 Cells - drug effects Caco-2 Cells - metabolism Carbapenems - pharmacology Drug toxicity and drugs side effects treatment Humans Imipenem Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Medical sciences Miscellaneous (drug allergy, mutagens, teratogens...) Panipenem Pharmacology. Drug treatments Valproic acid Valproic Acid - antagonists & inhibitors Valproic Acid - pharmacokinetics Valproic acid Caco-2 cell monolayer Panipenem Imipenem Human Drug combination Digestive system Toxicity Biological transport Permeation Oral administration Anticonvulsant In vitro Carbapenem derivatives Established cell line Drug interaction Antibacterial agent Mechanism of action Pharmacokinetics
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Summary:	The concomitant use of carbapenem antibiotics with valproic acid has been prohibited because carbapenems induced a decrease in plasma concentration of valproic acid in epileptic patients during valproic acid therapy. Our previous in vivo study in rats proposed that inhibition by carbapenem of the intestinal absorption of valproic acid might be a possible mechanism for the drug–drug interaction. To demonstrate the hypothesis, we examined the effects of imipenem and panipenem on intestinal transepithelial transport of valproic acid using Caco-2 cell monolayers. Imipenem and panipenem inhibited the transport of [ 14C]–valproic acid across the Caco-2 cell monolayers from apical-to-basolateral side in a concentration-dependent manner, although they had no effect on the uptake of [ 14C]–valproic acid by Caco-2 cells. The inhibition by the carbapenems of the valproic acid transport was found even when they were added to only the basolateral side. From these results, the carbapenems may inhibit the absorption of valproic acid at the basolateral membrane of intestinal epithelial cells, which contributes to the decrease in plasma concentration of valproic acid after oral administration.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0378-5173 1873-3476
DOI:	10.1016/S0378-5173(01)00916-4