Etoposide, a semi-synthetic derivative of podophyllotoxin, is widely used anticancer agent. Etoposide presents low bioavailability with wide inter-, and intra-patient variability after oral dosing. In an earlier study a piperine analogue, namely, 4-ethyl 5-(3, 4-methylenedioxyphenyl)-2E,4E-pentadienoic acid piperidide (PA-1), was shown to cause 2.32-fold enhancement of the absolute bioavailability of co-dosed etoposide in mice. In the present investigation a mechanistic evaluation was undertaken using various in vitro and animal-derived models. In everted rat gut sac studies PA-1 enhanced mucosal uptake of the drug while it inhibited efflux of Rh-123, a P-glycoprotein substrate from serosal-to-mucosal direction. In a single pass in situ perfusion experiment PA-1 significantly reduced the intestinal exsorption rate, exsorption clearance and the total plasma clearance of etoposide. On the other hand PA-1 did not alter the passive diffusion pattern of the drug in PAMPA assay. PA-1 was inhibitory to NADPH-assisted deethylation and demethylation reactions catalyzed by erythromycin N-demethylase, 7-methoxycoumarin-O-demethylase (MOCD) and ethoxyresorufin-O-deethylase (EROD). PA-1 was not cytotoxic to mucosal membrane and showed no adverse effect in acute toxicity determination. The results suggested that PA-1-mediated enhancement in the oral bioavailability of etoposide could possibly be due to its ability to modify P-gp/CYP 3A4 mediated drug disposition mechanisms.
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