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.
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 Emaxmodelling to derive; maximum effect (Emax) and concentration to exert 50% Emax effect (EC50). ZYDPLA1 showed rapid absorption, high volume of distribution, low clearance, and complete oral bioavailability. The Emaxderived after both routes and corresponding PK/PD profile showed comparable DDP-4 inhibition. The EC50for 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.
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Harilal
H
Patel
Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Amit A
AA
Joharapurkar
Department of Medicinal Chemistry, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Rajesh
R
Bahekar
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Prakash
P
Patel
Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Samadhan G
SG
Kshirsagar
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Nirav
N
Modi
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Ashok
A
Ghoghari
Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Vishal J
VJ
Patel
Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Mukul R
MR
Jain
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Nuggehally R
NR
Srinivas
Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Pankaj R
PR
Patel
Department of Medicinal Chemistry, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India.
Ranjit C
RC
Desai
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4