title: Transport and metabolism of opioid peptides across BeWo cells, an in vitro model of the placental barrier.
abstract: In keeping with the advance of biotechnology, cell culture becomes an important tool for investigating the transport and the metabolism phenomena. A cell line of human origin, the BeWo choriocarcinoma cell line, was used for the study of the transport and metabolism of opioid peptides across the in vitro model of the placental barrier. Opioid peptides, both naturally occurring and their synthetic analogs, are of interest to be developed as potent analgesics and were included in this study. The apparent permeability coefficients (Pe)s of the peptides containing 4-11 amino acid or analog residues were in the range of 0.23-14.6 x 10(-5) cm/s. The (Pe)s of these peptides were comparable to those of sucrose or dextrans, hydrophilic markers. The (Pe)s of low molecular weight (MW) peptides was not dependent on their MW or molecular size, whereas an inversely linear correlation between (Pe)s and molecular size was observed with the larger peptides. Molecular sieving of the BeWo monolayer restricted the transport of the peptides with MW> or =1033 Da or molecular size > or =6.6 A. Membrane partitioning ability and charge of the peptides were also investigated and found to be the minor factors regulating the extent of peptide permeation. Contrasting to the transport of Tyr-[D-pen-Gly-Phe-D-Pen] (DPDPE) peptide analog across the blood-brain barrier, the transport of DPDPE across the BeWo monolayers were not indicated to be via carrier-mediated transport. The major transport pathway of the opioid peptides across the BeWo monolayers was found to be via paracellular route. In metabolism studies, aminopeptidase was found to be a major enzyme type responsible for the degradation of naturally occurring peptides but not for the synthetic analogs. The finding obtained from the present study reveals the applicability of the BeWo cell line as an in vitro model for investigating placental transport and metabolism of opioid peptides.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Simons Laboratories, 2095 Constant Avenue, Lawrence, KS 66047, USA.
authors.forename: Chadarat
authors.initials: C
authors.lastname: Ampasavate
authors.forename: Gurudatt A
authors.initials: GA
authors.lastname: Chandorkar
authors.forename: David G
authors.initials: DG
authors.lastname: Vande Velde
authors.forename: John F
authors.initials: JF
authors.lastname: Stobaugh
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Audus
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002822:Choriocarcinoma / Q000378:metabolism; D004355:Drug Stability; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008970:Molecular Weight; D018847:Opioid Peptides / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D018847:Opioid Peptides; D020881:Enkephalin, D-Penicillamine (2,5)-