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Pharmacokinetics of dipeptidylpeptidase-4 inhibitors

DIABETES OBESITY & METABOLISM, Issue 8 2010
A. J. Scheen
Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug,drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [source]

Nucleotide-mediated calcium signaling in rat cortical astrocytes: Role of P2X and P2Y receptors

GLIA, Issue 3 2003
Marta Fumagalli
Abstract ATP is the dominant messenger for astrocyte-to-astrocyte calcium-mediated communication. Definition of the exact ATP/P2 receptors in astrocytes and of their coupling to intracellular calcium ([Ca2+]i) has important implications for brain physiology and pathology. We show that, with the only exception of the P2X6 receptor, primary rat cortical astrocytes express all cloned ligand-gated P2X (i.e., P2X1,5 and P2X7) and G-protein-coupled P2Y receptors (i.e., P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12). These cells also express the P2Y-like UDP-glucose receptor, which has been recently recognized as the P2Y14 receptor. Single-cell image analysis showed that only some of these receptors are coupled to [Ca2+]i. While ATP induced rapid and transient [Ca2+]i increases (counteracted by the P2 antagonists suramin, pyridoxal-phosphate-6-azophenyl-2,-4,-disulfonic acid and oxidized ATP), the P2X1/P2X3 agonist ,,meATP produced no changes. Conversely, the P2X7 agonist BzATP markedly increased [Ca2+]i; the presence and function of the P2X7 receptor was also confirmed by the formation of the P2X7 pore. ADP and 2meSADP also produced [Ca2+]i increases antagonized by the P2Y1 antagonist MRS2179. Some cells also responded to UTP but not to UDP. Significant responses to sugar-nucleotides were also detected, which represents the first functional response reported for the putative P2Y14 receptor in a native system. Based on agonist preference of known P2 receptors, we conclude that, in rat astrocytes, ATP-induced calcium rises are at least mediated by P2X7 and P2Y1 receptors; additional receptors (i.e., P2X2, P2X4, P2X5, P2Y2, P2Y4, and P2Y14) may also contribute. © 2003 Wiley-Liss, Inc. [source]

Theoretical study of CnCl, CnCl+, CnCl, (n=1,7) clusters

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 1 2001
Antonio Largo
Abstract A theoretical study of CnCl, CnCl+, and CnCl, (n=1,7) clusters has been carried out. Predictions for their electronic structures, dipole moments, and vibrational frequencies have been made at the B3LYP/6-311G(d) level. According to our calculations the lowest-lying geometry of all these species (with the only exception of neutral C3Cl) is predicted to be either a linear or quasi-linear structure with chlorine located at the end of the carbon chain. CnCl clusters all have doublet ground states, whereas the anionic clusters, with the only exception of CCl,, all have singlet ground states. For CnCl+ species, n -even clusters have triplet ground states whereas n -odd ones have singlet ground states. An even,odd parity effect (n -even clusters more stable than n -odd ones) is found for both the neutral and anionic species, whereas in the case of the cations the alternation in stability is reversed. The ionization potential (IP) and electron affinity (EA) also exhibit regular variations with the size of the cluster, with n -even clusters having both higher IP and EA than n -odd ones. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 84: 127,135, 2001 [source]

Expression of Messenger Ribonucleic Acid Encoding for Phosphodiesterase Isoenzymes in Human Female Genital Tissues

THE JOURNAL OF SEXUAL MEDICINE, Issue 6 2007
Stefan Uckert PhD
ABSTRACT Objectives., The use of inhibitors of phosphodiesterase 5 (PDE5) has been suggested to treat symptoms of female sexual dysfunction (FSD). Nonetheless, there has been a relatively low success rate of PDE5 inhibitors in FSD in comparison with male erectile dysfunction. The elevated expression of PDE5 in the human penile erectile tissue is considered the reason for the high clinical efficacy of PDE5 inhibitors in the pharmacotherapy of male erectile dysfunction. Aim., To evaluate by means of molecular biology the expression of messenger ribonucleic acid expression (mRNA) encoding for cyclic AMP and cyclic GMP PDE isoenzymes in female genital tissues. Main Outcome Measures., The amount of mRNA transcripts specifically encoding for cyclic AMP- and/or cyclic GMP-degrading PDE isoenzymes was determined. Methods., Human clitoral, labial, and vaginal tissue was obtained from four female cadavers (age at death: 18,42 years). The expression of mRNA specifically encoding for PDE1A, 1B, 1C, 2A, 4A, 5A, 10A, and 11A was elucidated by means of real-time polymerase chain reaction (PCR) analysis (TaqMan). Human penile erectile tissue (corpus cavernosum [HCC]) was used as a reference tissue. Results., mRNA encoding for all PDE isoforms mentioned above is expressed in the female genital tissues. Different magnitudes of mRNA expression were observed: a predominant expression of mRNA encoding for PDE1A but only insignificant amounts of PDE1B, 1C, 4A, 10, and 11A mRNA were registered. With PDE1A being the only exception, the mRNA expression was always higher in the HCC than in the female genital tissues. Especially, the expression of mRNA encoding for PDE5 was several-fold higher in the HCC. Conclusion., On the mRNA level, various PDE isoforms are expressed in the clitoris, labia, and vagina. It remains to be established as to whether the low expression of PDE5 in female genital tissue might be a negative predictor for the success of PDE5 inhibitors in the treatment of FSD. Uckert S, Ellinghaus P, Albrecht K, Jonas U, and Oelke M. Expression of messenger ribonucleic acid encoding for phosphodiesterase isoenzymes in human female genital tissues. J Sex Med 2007;4:1604,1609. [source]