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The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug–drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug–drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug–drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug–drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired. GLP-1 receptor agonists and DPP-4 inhibitors are focused on GLP-1, an incretin peptide stimulate secretion of insulin. The physiological disposition of them is of great significance. [Display omitted] [ABSTRACT FROM AUTHOR]

Hydroxymescaline (HM) and Β-phenylethylamine (PEA) affected the conditioned-avoidance responses (CAR) in rats after i.p. injection of 100 mg/kg and 40 mg/kg, respectively. The fates of these two compounds and of 2,3,4,5,6-pentamethoxyphenylethylamine (PMPEA), a behaviorally active mescaline derivative, and of 2,4,5-trimethoxyphenylethylamine (TMPEA), a behaviorally inactive compound, were studied in rats. All compounds are quickly absorbed and distributed after i.p. injection and are also quickly removed from brain, liver and plasma. The compounds cross the blood-brain barrier differently and TMPEA could not be detected in the CNS explaining, perhaps, its lack of behavioral activity. A comparison of the minimal doses (Μmoles/kg) of these compounds which affect the CAR in rats is: PMPEA (10)>mescaline (60)>PEA (240)>HM (420). In contrast, a comparison of minimal brain levels necessary to affect the CAR reveals the following relationship (nmoles/g) PMPEA (1.8)>mescaline (2.4)>Hm=PEA (40). It is suggested that SAR studies with psychoactive compounds should not be based on injected doses but on actual brain levels at periods of abnormal behavior. [ABSTRACT FROM AUTHOR]

Macromerine, normacromerine and bisnormacromerine, O and/or N methylated derivatives of norepinephrine, produce no effect on the conditioned avoidance response (CAR) in rats after IP injection of up to 100 mg/kg of the corresponding hydrochloride. The fate of these compounds was studied by a newly developed assay method utilizing an extraction procedure and the native fluorescence of the compounds. The compounds are rapidly absorbed from the peritoneal cavity, show a half-life of 30 to 60 min in plasma and liver, but remain rather unchanged in the brain during the first hour. Brain levels were found to be between 5 and 30 Μg/g. Since these brain levels are higher than those found for hallucinogenic compounds which do interfere with the CAR we conclude that these compounds are not or less psychoactive than known hallucinogenic substances. [ABSTRACT FROM AUTHOR]