title: Factors that restrict the cell permeation of cyclic prodrugs of an opioid peptide, part 4: Characterization of the biopharmaceutical and physicochemical properties of two new cyclic prodrugs designed to be stable to oxidative metabolism by cytochrome P-450 enzymes in the intestinal mucosa.
abstract: The biopharmaceutical and physicochemical properties of two new cyclic prodrugs (CA-[cychexalanine (Cha(4)), D-Leu(5) ]-Enkephalin (Enk) and coumarinic acid (CA)-[Cha(4), D-Ala(5)]-Enk) of opioid peptides that were designed to be stable to oxidative metabolism by cytochrome P-450 enzymes in the intestinal mucosa are described in this paper. Two-dimensional nuclear magnetic resonance studies and molecular dynamics simulations showed that these cyclic prodrugs exhibit unique solution conformations (i.e., type I β-turns), which are favorable for transcellular permeation. The calculated molecular surface areas and cLog P values confirmed that these new cyclic prodrugs are more lipophilic than linear opioid peptides and, thus, they should exhibit better transcellular permeation characteristics. However, Caco-2 cell permeation studies showed that the cyclic prodrugs were substrates for apically polarized efflux transporters (e.g., P-glycoprotein, which significantly limited their transcellular permeation). Permeability studies using an in situ rat intestinal perfusion model confirmed the poor intestinal permeation characteristics of CA-[Cha(4), D-Leu(5) ]-Enk and CA-[Cha(4), D-Ala(5)]-Enk as well as the stability of these two new cyclic prodrugs of opioid peptides to oxidative metabolism. In conclusion, these data clearly show that oral absorption of cyclic prodrugs of opioid peptides can only be achieved by designing molecules devoid of substrate activity for both cytochrome P-450 enzymes and efflux transporters in the intestinal mucosa.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA. Rebecca_Nofsinger@Merck.com
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nofsinger
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Borchardt
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D004355:Drug Stability; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D010477:Perfusion; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000701:Analgesics, Opioid; D011355:Prodrugs; D016308:Enkephalin, Leucine-2-Alanine; D003577:Cytochrome P-450 Enzyme System