Is the Inhibition of Dipeptidyl Peptidase-4 (DDP-4) Enzyme Route Dependent and/or Driven by High Peak Concentration?– Seeking Answers with ZYDPLA1, a Novel Long Acting DPP-4 Inhibitor, in a Rodent Model
| Autor: | Ranjit C. Desai, Mukul R. Jain, Vishal Patel, Amit Joharapurkar, Ashok Ghoghari, Pankaj R. Patel, Prakash Patel, Harilal Patel, Nuggehally R. Srinivas, Nirav Modi, Samadhan Kshirsagar, Rajesh Bahekar |
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| Rok vydání: | 2017 |
| Předmět: |
Male
Dipeptidyl Peptidase 4 Administration Oral Biological Availability 030209 endocrinology & metabolism 02 engineering and technology Absorption (skin) Pharmacology Diabetes Mellitus Experimental 03 medical and health sciences Route of administration 020210 optoelectronics & photonics 0302 clinical medicine Pharmacokinetics Oral administration Drug Discovery 0202 electrical engineering electronic engineering information engineering Animals Humans Hypoglycemic Agents Rats Wistar Dipeptidyl peptidase-4 Volume of distribution Dipeptidyl-Peptidase IV Inhibitors Chemistry General Medicine Rats Bioavailability Diabetes Mellitus Type 2 Area Under Curve Pharmacodynamics Administration Intravenous Half-Life |
| Zdroj: | Drug Research. 67:223-227 |
| ISSN: | 2194-9387 2194-9379 |
| Popis: | ZYDPLA1 is a long acting enzyme dipeptidyl peptidase-4 (DPP-4) inhibitor. The comparative effect of DPP-4 inhibition after intravenous (IV) and oral administration of ZYDPLA1 in a rat model was evaluated to answer the question of route dependency and/or the need of high plasma levels of ZYDPLA1. The study was conducted using parallel design in male Wistar rats for IV/oral route (n=9 and 6, for IV and oral respectively). A single 30 mg/kg dose of ZYDPLA1 was administered. Plasma samples were analysed for ZYDPLA1 concentration and DPP-4 inhibition. Pharmacokinetic analysis was carried out to assess peak concentration, area under the concentration–time curve, total body clearance, elimination half-life, and mean residence time. The PK/PD correlation was performed using standard sigmoidal E max modelling to derive; maximum effect (E max ) and concentration to exert 50% Emax effect (EC 50 ). ZYDPLA1 showed rapid absorption, high volume of distribution, low clearance, and complete oral bioavailability. The E max derived after both routes and corresponding PK/PD profile showed comparable DDP-4 inhibition. The EC 50 for IV (0.021 µg/mL) was comparable to the oral route (0.019 µg/mL). ZYDPLA1 showed full DPP-4 inhibition without regard to the route of administration. Higher systemic peak levels showed no bearing on the DDP-4 inhibition. |
| Databáze: | OpenAIRE |
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