NDLI: Acyloxyalkoxy-Based Cyclic Prodrugs of Opioid Peptides: Evaluation of the Chemical and Enzymatic Stability as Well as Their Transport Properties Across Caco-2 Cell Monolayers

Content Provider	Springer Nature Link
Author	Bak, Annette Gudmundsson, Olafur S. Friis, Gitte J. Siahaan, Teruna J. Borchardt, Ronald T.
Copyright Year	1999
Abstract	Purpose. To evaluate the chemical and enzymatic stability, as well as the cellular permeation characteristics, of the acyloxyalkoxy-based cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ of the opioid peptides [Leu$^{5}$]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively. Methods. The rates of conversion of $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ to [Leu$^{5}$]-enkephalin and DADLE, respectively, were measured by HPLC in HBSS, pH = 7.4, and in various biological media (e.g., human plasma and Caco-2 cell and rat liver homogenates) having measurable esterase activity. The cellular permeation and metabolism characteristics of [Leu$^{5}$]-enkephalin, DADLE and the cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were measured using Caco-2 cell monolayers grown onto microporous membranes and monitored by HPLC. Results. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ degraded slowly but stoichiometrically to [Leu$^{5}$]-enkephalin and DADLE, respectively, in HBSS, pH = 7.4. In homogenates of Caco-2 cells and rat liver, as well as 90% human plasma, the rates of disappearance of the cyclic prodrugs were significantly faster than in HBSS. The stabilities of the cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ were increased significantly in 90% human plasma and Caco-2 cell homogenates when paraoxon, a potent inhibitor of serine-dependent esterases, was included in the incubation mixtures. A similar stabilizing effect of paraoxon was not observed in 50% rat liver homogenates, but was observed in 10% homogenates of rat liver. When applied to the AP side of a Caco-2 cell monolayer, DADLE and cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ exhibited significantly greater stability than [Leu$^{5}$]-enkephalin. Based on their physicochemical properties (i.e., lipophilicity), cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ should have exhibited high permeation across Caco-2 cell monolayers. Surprisingly, the AP-to-BL apparent permeability coefficients (P$_{App}$) for cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ across Caco-2 cell monolayers were significantly lower than the P$_{App}$ value determined for the metabolically stable opioid peptide DADLE. When the P$_{App}$ values for cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ crossing Caco-2 cell monolayers in the BL-to-AP direction were determined, they were shown to be 36 and 52 times greater, respectively, than the AP-to-BL values. Conclusions. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , prepared with an acyloxyalkoxy promoiety, were shown to degrade in biological media (e.g., 90% human plasma) via an esterase-catalyzed pathway. The degradation of cyclic prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ , which contained an ester formed with an L-amino acid, degraded more rapidly in esterase-containing media than did prodrug $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ , which contained an ester formed with a D-amino acid. Cyclic prodrugs $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{1} $$ and $$\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle-}$}}{2} $$ showed very low AP-to-BL Caco-2 cell permeability, which did not correlate with their lipophilicities. These low AP-to-BL permeabilities result because of their substrate activity for apically polarized efflux systems.
Starting Page	24
Ending Page	29
Page Count	6
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	16
Issue Number	1
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	1999-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Transepithelial Transport of Prodrugs of the HIV Protease Inhibitors Saquinavir, Indinavir, and Nelfinavir Across Caco-2 Cell Monolayers

Characterization of Mefenamic Acid-Guaiacol Ester: Stability and Transport Across Caco-2 Cell Monolayers

Transport of Proteolytic Enzymes Across Caco-2 Cell Monolayers

Phenylpropionic Acid-Based Cyclic Prodrugs of Opioid Peptides that Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeation

Coumarinic Acid-Based Cyclic Prodrugs of Opioid Peptides that Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeability

Carrier-Mediated Transport of Macrolide Antimicrobial Agents Across Caco-2 Cell Monolayers

Transport Characteristics of Peptidomimetics. Effect of the Pyrrolinone Bioisostere on Transport Across Caco-2 Cell Monolayers

Transepithelial Transport of Diphenhydramine Across Monolayers of the Human Intestinal Epithelial Cell Line Caco-2

Characterization of the Transport of Uracil Across Caco-2 and LLC-PK$_{1}$ Cell Monolayers

Acyloxyalkoxy-Based Cyclic Prodrugs of Opioid Peptides: Evaluation of the Chemical and Enzymatic Stability as Well as Their Transport Properties Across Caco-2 Cell Monolayers

Similar Documents

Transepithelial Transport of Prodrugs of the HIV Protease Inhibitors Saquinavir, Indinavir, and Nelfinavir Across Caco-2 Cell Monolayers

Characterization of Mefenamic Acid-Guaiacol Ester: Stability and Transport Across Caco-2 Cell Monolayers

Transport of Proteolytic Enzymes Across Caco-2 Cell Monolayers

Phenylpropionic Acid-Based Cyclic Prodrugs of Opioid Peptides that Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeation

Coumarinic Acid-Based Cyclic Prodrugs of Opioid Peptides that Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeability

Carrier-Mediated Transport of Macrolide Antimicrobial Agents Across Caco-2 Cell Monolayers

Transport Characteristics of Peptidomimetics. Effect of the Pyrrolinone Bioisostere on Transport Across Caco-2 Cell Monolayers

Transepithelial Transport of Diphenhydramine Across Monolayers of the Human Intestinal Epithelial Cell Line Caco-2

Characterization of the Transport of Uracil Across Caco-2 and LLC-PK$_{1}$ Cell Monolayers

Acyloxyalkoxy-Based Cyclic Prodrugs of Opioid Peptides: Evaluation of the Chemical and Enzymatic Stability as Well as Their Transport Properties Across Caco-2 Cell Monolayers