title: Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin.
abstract: Bestatin is an immunomodulator with antitumor activity. This study was performed to investigate the effect of P-gp on the intestinal absorption and antiproliferative activity of bestatin. Our results showed that P-gp inhibitors significantly increased rat intestinal absorption of bestatin in vivo and in vitro. The net efflux ratio of bestatin was 2.2 across mock-/MDR1-MDCK cell monolayers and was decreased by P-gp inhibitors, indicating bestatin was a substrate of P-gp. Furthermore, the IC50 values of bestatin on U937 and K562 cells were decreased dramatically and the intracellular concentrations of bestatin were increased by incubation of cells with verapamil or Cyclosporin A. K562/ADR cells exhibited a higher IC50 value and a lower intracellular level of bestatin. The bestatin level in K562/ADR cells was partially restored by incubation with doxorubicin. However, P-gp and APN mRNA levels were not changed by bestatin. These results suggested that the intestinal absorption and accumulation in cancer cells for bestatin were limited by P-gp-mediated efflux. Additional attention should be paid to the alternative exposure of bestatin when bestatin was coadministered with drugs as P-gp substrates in clinic.
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: huoxiaokui@163.com.
authors: Xiaokui
authors: X
authors: Huo
authors: Qi
authors: Q
authors: Liu
authors: Changyuan
authors: C
authors: Wang
authors: Qiang
authors: Q
authors: Meng
authors: Huijun
authors: H
authors: Sun
authors: Jinyong
authors: J
authors: Peng
authors: Xiaochi
authors: X
authors: Ma
authors: Kexin
authors: K
authors: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018826:CD13 Antigens / Q000235:genetics; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D020014:K562 Cells; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D017208:Rats, Wistar; D020298:U937 Cells; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D016572:Cyclosporine; D014700:Verapamil; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex
keywords: ADR; AUC; Antiproliferative activity; Bestatin; CLp; CsA; Cyclosporin A; DDI; H(+)/peptide transporter; Intestinal absorption; KRB; Krebs–Ringer buffer; MDR; MRP2; OAT; OCT; P-glycoprotein; P-gp; PEPT; Ver; adriamycin; area under the plasma concentration-time curve; drug–drug interaction; multidrug resistance; multidrug resistance-associated protein 2; organic anion transporter; organic cation transporter; plasma clearance rate; verapamil hydrochloride