ABSTRACT
The creation of a pharmacokinetic (PK) curve, which follows the plasma concentration of an administered drug as a function of time, is a critical aspect of the drug development process and includes such information as the drug's bioavailability, clearance, and elimination half-life. Prior to a drug of interest gaining clearance for use in human clinical trials, research is performed during the preclinical stages to establish drug safety and dosing metrics from data obtained from the PK studies. Both in vivo animal models and in vitro platforms have limitations in predicting human reaction to a drug due to differences in species and associated simplifications, respectively. As a result, in silico experiments using computer simulation have been implemented to accurately predict PK parameters in human studies. This review assesses these three approaches (in vitro, in vivo, and in silico) when establishing PK parameters and evaluates the potential for in silico studies to be the future gold standard of PK preclinical studies.
Subject(s)
Models, Biological , Pharmaceutical Preparations/analysis , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Animals , Humans , Pharmaceutical Preparations/bloodABSTRACT
Type 1 diabetes is associated with such complications as blindness, kidney failure, and nerve damage. Replacing C-peptide, a hormone normally co-secreted with insulin, has been shown to reduce diabetes-related complications. Interestingly, after nearly 30 years of positive research results, C-peptide is still not being co-administered with insulin to diabetic patients. The following review discusses the potential of C-peptide as an auxilliary replacement therapy and why it's not currently being used as a therapeutic.
Subject(s)
C-Peptide/therapeutic use , Diabetes Complications/therapy , Diabetes Mellitus, Type 1/therapy , Insulin/therapeutic use , Animals , Bibliometrics , C-Peptide/deficiency , C-Peptide/history , C-Peptide/pharmacokinetics , Clinical Trials as Topic , Diabetes Complications/history , Diabetes Complications/metabolism , Diabetes Complications/pathology , Diabetes Mellitus, Type 1/history , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Disease Models, Animal , History, 20th Century , History, 21st Century , Humans , Insulin/deficiency , Insulin/history , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Iron/metabolism , Protein Binding , Serum Albumin/metabolism , Serum Albumin/pharmacokinetics , Zinc/metabolismABSTRACT
AIMS/HYPOTHESIS: Proinsulin C-peptide has been implicated in reducing complications associated with diabetes and also in improving blood flow. We hypothesised that incubation of erythrocytes with C-peptide would improve the ability of these cells to release ATP, a stimulus for nitric oxide production. METHODS: Erythrocytes obtained from rabbits (n = 11) and both healthy and type 2 diabetic humans (n = 7) were incubated with C-peptide in the absence and presence of Fe2+ and Cr3+, and the resulting ATP release was measured via chemiluminescence. This release was also measured in the presence and absence of phloretin, an inhibitor of GLUT1, and also of mannose, a glycolysis inhibitor. To determine glucose transport, 14C-labelled glucose was added to erythrocytes in the presence and absence of the C-peptide-metal complex and the aforementioned inhibitors. RESULTS: The release of ATP from the erythrocytes of patients with diabetes increased from 64 +/- 13 to 260 +/- 39 nmol/l upon incubation of the cells in C-peptide. The C-peptide activity was dependent upon binding to Fe2+, which was extended upon binding to Cr3+. The increase in ATP release from the erythrocytes is due to metal-activated C-peptide stimulation of glucose transfer into the erythrocytes via the GLUT1 transporter. In the presence of C-peptide complexed to Cr3+, the amount of glucose transferred into the erythrocyte increased by 31%. CONCLUSIONS/INTERPRETATION: When complexed to Fe2+ or Cr3+, C-peptide has the ability to promote ATP release from erythrocytes. This release is due to an increase in glucose transport through GLUT1.
