Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

The Inhibitory Effect Of Glutathione On Buccal Enzymatic Degradation Of Therapeutic Peptides (leu-enkephalin, Luteinizing Hormone-releasing Hormone And Pituitary Adenylate Cyclase Activating Peptide)

N. Langoth, A. Bernkop-Schnürch, P. Kurka
Published 2005 · Chemistry

Save to my Library
Download PDF
Analyze on Scholarcy
Share
The purpose of this study was to evaluate the potential of glutathione (GSH) as an auxiliary agent for buccal drug delivery system s to protect therapeutic peptides from enzymatic degradation. Stability of the model peptide drugs leu-enkephalin (Leu-Enke), luteinizing hormone-releasing hormone (LHRH) and pituitary adenylate cyclase activating peptide (PACAP) in the absence and presence of GSH on degradation by buccal enzymes was investigated. Inhibition studies were performed with isolated aminopeptidase N representing the most abundant peptidase on the buccal mucosa and on excised intact buccal mucosa from pigs. Enzymatic degradation of peptides was quantified by HPLC. The absorption of GSH across freshly excised porcine buccal mucosa was studied using Ussing type diffusion chambers. The proteolytic activity of isolated aminopeptidase N was significantly inhibited by the addition of 2% (m/v) GSH. Without the addition of enzyme inhibitors Leu-Enke was completely degraded by aminopeptidase N, whereas 34.8 ± 27.2% of LHRH and 74.2 ± 12.0% of PACAP remained intact. In contrast, by the addition of 2% (m/v) GSH 33.2 ± 2.2% of Leu-Enke, 88.6 ± 12.8% of LHRH and 97.0 ± 6.2% of PACAP remained stable after 5 h of incubation. Additionally, it was shown that only 0.2 ± 0.0% of GSH was able to permeate the buccal mucosa within 5 h, demonstrating that GSH remains concentrated at the site of drug absorption. After incubation for 5 h on the buccal mucosa 0.8 ± 0.2% of Leu-Enke, 73.2 ± 6.6% of LHRH and 82.9 ± 8.8% of PACAP remained stable. In contrast, in the presence of 2% (m/v) GSH 103.1 ± 12.7% of Leu-Enke, 98.5% ± 5.4% of LHRH and 97.2 ± 4.2% of PACAP were stable. According to these results GSH seems to represent a promising inhibitor for the buccal administration of peptide drugs.
This paper references
10.2337/DIABETES.51.5.1453
A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes.
M. Tsutsumi (2002)
10.1023/A:1018973029651
Prodrugs of Peptides. 18. Synthesis and Evaluation of Various Esters of Desmopressin (dDAVP)
A. H. Kahns (2004)
10.1016/S0378-5173(01)00934-6
Peptidase activity on the surface of the porcine buccal mucosa.
G. Walker (2002)
10.1093/TOXSCI/51.2.161
Symposium overview: the role of glutathione in neuroprotection and neurotoxicity.
T. Monks (1999)
10.1016/S0168-3659(01)00269-3
Drug permeation enhancement via buccal route: possibilities and limitations.
S. Şenel (2001)
10.3109/10837459609022593
Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced transmucosal permeation.
S. Nakane (1996)
10.1016/0024-3205(86)90150-5
Enkephalin hydrolysis in homogenates of various absorptive mucosae of the albino rabbit: similarities in rates and involvement of aminopeptidases.
S. D. Kashi (1986)
10.1023/A:1015936426906
Gastrointestinal Transit of Nondisintegrating, Nonerodible Oral Dosage Forms in Pigs
M. Hossain (2004)
10.1016/0378-5173(86)90137-7
Aminopeptidase activity in homogenates of various absorptive mucosae m the albino rabbit: implications in peptide delivery
R. Stratford (1986)
10.1016/0024-3205(90)90492-A
Insulin and proinsulin proteolysis in mucosal homogenates of the albino rabbit: implications in peptide delivery from nonoral routes.
A. Yamamoto (1990)
10.1023/A:1015345827091
The Role of Glutathione in the Permeation Enhancing Effect of Thiolated Polymers
A. Clausen (2004)
10.1016/0169-409X(89)90018-5
Penetration and enzymatic barriers to peptide and protein absorption
V. Lee (1989)
10.1016/S0939-6411(00)00144-2
Factors and strategies for improving buccal absorption of peptides.
F. Veuillez (2001)
10.1021/BI00713A005
Human liver aminopeptidase. Role of metal ions in mechanism of action.
C. W. Garner (1974)
10.1016/0162-0134(83)80018-X
Kinetics and mechanism of Zn(II) complexation with reduced glutathione.
L. Dominey (1983)
10.1002/JPS.2600821124
Transmucosal delivery of leucine enkephalin: stabilization in rabbit enzyme extracts and enhancement of permeation through mucosae.
A. Sayani (1993)
10.1023/A:1018962415287
Oral Absorption of Peptides: The Effect of Absorption Site and Enzyme Inhibition on the Systemic Availability of Metkephamid
P. Langguth (2004)



This paper is referenced by
Semantic Scholar Logo Some data provided by SemanticScholar