Tremendous progress has been made in recent years in the design and synthesis of peptides and peptidomimetics with high affinity and high selectivity for the different types (mu, delta, kappa) of opioid peptides. However, the clinical development of these synthetic opioid peptides and peptidomimetics has been seriously limited by their poor biopharmaceutical properties (e.g. low permeation through the intestinal mucosa and the blood-brain barrier). With support from this NIDA grant, we have designed and synthesized esterase-sensitive cyclic prodrugs of a model opioid peptide (DADLE) that exhibit physicochemical properties (hydrophobicity, low hydrogen bonding potential, no charge) favorable for high transcellular permeation. However, these cyclic prodrugs were shown to exhibit substrate activity for efflux transporters (e.g. MDR1, MRP2) which restrict their permeation across the intestinal mucosa and the blood-brain barrier. If these efflux transporters in the blood-brain barrier are inhibited, the """"""""intrinsic"""""""" permeability coefficients (Papp) of these cyclic prodrugs are 100-300 fold higher than the Papp value for DADLE itself. Based on these exciting observations, we plan during the next grant period to focus on the optimization of the bio-pharmaceutical properties of the cyclic prodrugs, including: (i) minimizing their substrate activity for the efflux transporters that limit their intestinal mucosal and blood-brain barrier permeation while maintaining their good """"""""intrinsic"""""""" permeation characteristics; (ii) optimizing their conversion to DADLE in the target tissue (brain) and minimizing their conversien in the blood compartment; and (iii) minimizing their clearance by the liver so as to increase their residency time in the blood, thus maximizing the opportunity for the prodrug to partition across the blood-brain barrier. The results of the studies proposed in this renewal application should allow for the design of second generation cyclic prodrugs of opioid peptides that will afford optimal pharmacological effects after i.v. or oral administration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009315-10
Application #
6913385
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Hillery, Paul
Project Start
1995-07-09
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
10
Fiscal Year
2005
Total Cost
$254,625
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E et al. (2009) Factors that restrict the intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE): Part I. Role of efflux transporters in the intestinal mucosa. J Pharm Sci 98:337-48
Ouyang, Hui; Andersen, Thomas E; Chen, Weiqing et al. (2009) A comparison of the effects of p-glycoprotein inhibitors on the blood-brain barrier permeation of cyclic prodrugs of an opioid peptide (DADLE). J Pharm Sci 98:2227-36
Ouyang, Hui; Chen, Weiqing; Andersen, Thomas E et al. (2009) Factors that restrict intestinal cell permeation of cyclic prodrugs of an opioid peptide (DADLE): Part II. Role of metabolic enzymes in the intestinal mucosa. J Pharm Sci 98:349-61
Liederer, Bianca M; Fuchs, Tarra; Vander Velde, David et al. (2006) Effects of amino acid chirality and the chemical linker on the cell permeation characteristics of cyclic prodrugs of opioid peptides. J Med Chem 49:1261-70
Tang, Fuxing; Ouyang, Hui; Yang, Jerry Z et al. (2004) Bidirectional transport of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein, across MDCK-MDR1 cell monolayers. J Pharm Sci 93:1185-94
Horie, Kazutoshi; Tang, Fuxing; Borchardt, Ronald T (2003) Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance protein efflux transporter. Pharm Res 20:161-8
Chen, Weiqing; Yang, Jerry Z; Andersen, Rikke et al. (2002) Evaluation of the permeation characteristics of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs across the blood-brain barrier using an in situ perfused rat brain model. J Pharmacol Exp Ther 303:849-57
Yang, Jerry Z; Bastian, K Chad; Moore, Randy D et al. (2002) Quantitative analysis of a model opioid peptide and its cyclic prodrugs in rat plasma using high-performance liquid chromatography with fluorescence and tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 780:269-81
Ouyang, Hui; Tang, Fuxing; Siahaan, Teruna J et al. (2002) A modified coumarinic acid-based cyclic prodrug of an opioid peptide: its enzymatic and chemical stability and cell permeation characteristics. Pharm Res 19:794-801
Tang, Fuxing; Horie, Kazutoshi; Borchardt, Ronald T (2002) Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res 19:765-72

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