title: Involvement of P-glycoprotein and CYP 3A4 in the enhancement of etoposide bioavailability by a piperine analogue.
abstract: 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.
authors.affiliation: PK PD Toxicology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-Tawi, JK 180001, India.
authors.forename: I A
authors.initials: IA
authors.lastname: Najar
authors.forename: S C
authors.initials: SC
authors.lastname: Sharma
authors.forename: G D
authors.initials: GD
authors.lastname: Singh
authors.forename: S
authors.initials: S
authors.lastname: Koul
authors.forename: P N
authors.initials: PN
authors.lastname: Gupta
authors.forename: S
authors.initials: S
authors.lastname: Javed
authors.forename: R K
authors.initials: RK
authors.lastname: Johri
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000042:Absorption; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D002463:Cell Membrane Permeability / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D005047:Etoposide / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: C559744:4-ethyl 5-(3,4 methylenedioxyphenyl)-2E,4E-pentadienoic acid piperidine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D010880:Piperidines; D005047:Etoposide; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A