Effect of hydroxyzine on the transport of etoposide in rat small intestine

Etoposide, an anti-neoplastic agent and a substrate of P-glycoprotein (P-gp ), exhibits variable oral bioavailability. P-gp, the multidrug resistance g ene (mdr1) product, has been considered as an absorption barrier against in testinal drug absorption. Terfenadine, an antihistamine, has been shown to be a P-gp inhibitor. The current study was designed to assess the effect of hydroxyzine, an antihistamine, on the transport of etoposide in the small intestine. Everted rat gut sacs were used to determine the absorption and e xsorption of etoposide under different conditions, as rhodamine 123 was cho sen to evaluate the role of P-gp in the drug interaction. The results showe d that the transport of etoposide was significantly increased from the lumi nal site to the serosal site in the jejunum by 2- and 4-fold after 90 min i n the presence of hydroxyzine and quinidine, respectively. A similar trend was observed in the ileal sacs. This in vitro exsorption study also demonst rated that hydroxyzine could reduce the efflux of etoposide to the luminal site in either jejunum or ileum. The effect of hydroxyzine on the pharmacok inetics of etoposide differed by the in vivo route of administration, thus assuming clinical importance for chemotherapeutic treatment. [(C) 2001 Lipp incott Williams & Wilkins].