| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 88 === Multidrug resistance (MDR) represents a major obstacle in the therapy of neoplastic disease. P-glycoprotein (Pgp), the mdr1 gene encoding membrane protein, plays an important role. It acts as an energy-dependent efflux pump to remove various chemotherapy drugs out of cells. Pgp is expressed in numerous tumor cells as well as in normal tissues including the small intestine brush-border membrane. The objective of this study is to investigate the effects of Pgp inhibitors on oral drug absorption.
Etoposide, an oral chemotherapeutic agent with erratic oral bioavailability, has confirmed to be a Pgp substrate. Therefore, etoposide is chosen to study the interaction between Pgp substrates and inhibitors. ALLN (N-acetyl-leu-leu-norleucinal), is a synthetic peptide that was shown to stimulate Pgp ATPase activity in vitro. Therefore, everted gut sacs was applied to study the absorption of etoposide in rats.
The results showed that the transport of etoposide was increased by the addition of 500 mM ALLN in the rat everted gut sacs. After 90 minutes, the concentrations of etoposide in jejunal and ileal sacs were 17.41±4.36→44.18±7.80 mg/ml and 8.55±1.55→35.11±5.56 mg/ml, respectively. This implies that the increased absorption of etoposide by ALLN may be related to Pgp. To further investigate the effects of Pgp on drug therapy in human, fragments of Pgp (PgpA, PgpB) were cloned from human small intestine cDNA.
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