Journal article
Nasal pre-systemic metabolism of peptide drugs: Substance P metabolism in the sheep nasal cavity
International journal of pharmaceutics, Vol.128(1), pp.229-237
1996
DOI: 10.1016/0378-5173(95)04313-6
Abstract
Although the nasal administration of peptide and protein drugs bypasses hepatic first-pass metabolism and the highly proteolytic environment in the gastrointestinal tract, the enzymes present in the nasal cavity may still limit the bioavailability of peptide and protein compounds. A knowledge of the degradation patterns in both the nasal secretions and homogenates is important to estimate bioavailability limitations resulting from pre-systemic metabolism. Substance P (SP) and its fragments SP(1–9), and SP(1–7) were incubated with both nasal secretions and homogenized mucosal tissues to investigate peptide metabolism in the sheep nasal cavity. The disappearance of the initial peptide compounds and appearance of their metabolites were analyzed by reverse phase HPLC. The metabolism patterns in the secretions were found to be similar to those in the homogenates. SP(1–9) and SP(1–7) were the two major fragments identified for the degradation of SP. SP(1–9) was also further metabolized to SP(1–7). The order of the degradation rates was SP ≈ SP(1–9) > SP(1–7) in both the homogenates and secretions. No major C-terminal fragments, such as SP(2–11) and SP(3–11), were found which suggests that SP, SP(1–9) and SP(1–7) are resistant to the activity of the aminopeptidases present in the nasal cavity. Addition of phosphoramidon, a specific inhibitor of neutral endopeptidase 24.11 (NEP), to the reaction mixtures reduced the pseudo-first order rate constants by 72 and 90% in nasal homogenates and nasal secretions, respectively. Captopril, an inhibitor of angiotensin converting enzyme (ACE), did not inhibit SP metabolism in either secretions or homogenates.
Details
- Title: Subtitle
- Nasal pre-systemic metabolism of peptide drugs: Substance P metabolism in the sheep nasal cavity
- Creators
- Francis Y. ChungMaureen D. Donovan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of pharmaceutics, Vol.128(1), pp.229-237
- Publisher
- Elsevier B.V
- DOI
- 10.1016/0378-5173(95)04313-6
- ISSN
- 0378-5173
- eISSN
- 1873-3476
- Language
- English
- Date published
- 1996
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984366014002771
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