Charakterisierung der Eliminationskinetik des glukagonähnlichen Peptids-1 als Substrat der Dipeptidyl-Peptidase-IV mit und ohne Enzymhemmung am Modell der Ratte

Sandel, Jan Peter (2005): Charakterisierung der Eliminationskinetik des glukagonähnlichen Peptids-1 als Substrat der Dipeptidyl-Peptidase-IV mit und ohne Enzymhemmung am Modell der Ratte: (Characterisation of elimination kinetics of glucagon-like peptide-1 as substrate of dipeptidyl-peptidase-IV with and without enzyme inhibition in the rat model). Dissertation, LMU München: Tierärztliche Fakultät

Abstract

Orally and intravenously administered glucose yields comparable levels of glucose in plasma but different responses of insulin-release. Specialised mucosa cells react to glucose contents in chyme with release of glucagon-like peptide-1 (GLP-1) into the portal bloodstream, a peptide hormone, that makes beta-cells more sensitive to the subsequent glucose stimulus and thereby enhances the insulin-release exclusively under increased blood glucose levels without causing the insulin-release directly. The capacity of this entero-insular axis is limited primarily by the endogenous enzyme dipeptidyl peptidase IV (DPP-IV). Prevailingly the most progressive approach to therapy of non-insulin-dependent diabetes mellitus (NIDDM) in human medicine is targeted on the inhibition of DPP-IV, in order to raise GLP-1 concentration in plasma and to increase consequently the insulin-release in dependence on elevated blood glucose levels. In the limelight of discussion are the advantages of certain avoidance of insulin-caused hypoglycaemia on the one hand and the possibility of oral administration of the antienzyme on the other hand. In contrast to the condition in dogs, where the disease manifests almost exclusively in the form of secondary (insulin-dependent) diabetes mellitus, the type 2 (NIDDM) predominates in humans as well as in cats, whence it comes that the employment of oral antidiabetics in the latter species is quite promising, as the experience with the sulfonyl urea derivative glipizide has shown. As however the residual capacity of beta-cells of feline diabetics with regard to the release of endogenous insulin is subject to considerable variation, the risk of inducing hypoglycaemia is given by use of both insulin and sulfonyl urea derivatives, whereas this threat is circumvented by use of DPP-IV-inhibitors. In the present thesis the effect of DPP-IV inhibition on the elimination kinetics of GLP-1 is described by means of systematically combined infusion of the enzyme’s substrate (GLP-1) and its antienzyme in the rat model. The maximum effective dose of DPP-IV inhibitor is determined and the portion of hepatic clearance and whole blood clearance of total elimination of GLP-1 without concurrent DPP-IV inhibition is quantified approximately by means of isolated perfused rat livers and in-vitro-experiments. Finally the dependence of results on the respective experimental design is demonstrated. The total clearance of GLP-1 as substrate of DPP-IV without concurrent inhibition amounts to at least 57 ± 17 (mL/min)/kg and under influence of the DPP-IV-inhibitor to at least 22 ± 2 (mL/min)/kg. The value of clearance is highly dependent on the respective substrate concentration in plasma, so that the values range from 139 ± 57 (mL/min)/kg to 73 ± 15 (mL/min)/kg within the bounds of physiological GLP-1 concentrations in plasma. The maximum increase of GLP-1 levels in plasma (factor 3.4) on average of all GLP-1 infusion rates was attained by a DPP-IV inhibitor concentration in plasma of 0.4 µmol/L. The liver as central detoxication-organ figures out at 57 % (34/60) of total clearance, the soluble DPP-IV fraction in plasma however accounts for only about 1 % (0.7/60) of total clearance. The relatively low hepatic extraction ratio of 30 ± 11 % reversely allows seven out of ten GLP-1 molecules to enter the systemic circulation in spite of the first-pass-effect and thereby to reach possibly the receptors on the beta-cells (70 % bioavailability). The half-life of GLP-1 (7-36 amide) in the isolated perfused rat liver amounts to 5.0 ± 1.3 minutes, hereby differing statistically not significantly (p = 0.114) from the half-life of GLP-1 (7-37) with 6.1 ± 1.6 minutes.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: pharmacokinetics, oral antidiabetics, glucagon-like peptide-1, dipeptidyl-peptidase-IV, isolated perfused rat liver
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 590 Tiere (Zoologie)
• Fakultäten: Tierärztliche Fakultät
• Sprache der Hochschulschrift: Deutsch
• Datum der mündlichen Prüfung: 11. Februar 2005
• 1. Bericht­erstatter:in: Schulz, Rüdiger