title: Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: roles of P-glycoprotein and cytochrome P450 3A inhibition.
abstract: Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced intestinal absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and intestinal metabolism. In vitro Caco-2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ intestinal absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS>Cremophor EL-based SMEDDS>Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0-t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the intestinal absorption of P-gp and/or CYP3A substrate drugs.
authors: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
authors: Gang
authors: G
authors: Zhao
authors: Jiangeng
authors: J
authors: Huang
authors: Kewen
authors: K
authors: Xue
authors: Luqin
authors: L
authors: Si
authors: Gao
authors: G
authors: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D016503:Drug Delivery Systems; D005047:Etoposide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; D005047:Etoposide; D014700:Verapamil; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole
keywords: Absorption; Cytochrome P450 3A; Etoposide; P-glycoprotein; Self-microemulsifying drug delivery system