The ion sensitive field effect transistors (ISFETs) have been increasingly used in physiological data acquisition and environmental monitoring in recent years. The pH monitoring of river, waste water or urine has become more important in daily life. In order to investigate the read-out circuit performance due to non-ideal characteristics of ISFETs, this work develops a behavioral macromodel for a depletion-mode ion sensitive field effect transistor with a silicon nitride gate-insulator. This model included co-design of the bridge-type floating source interface circuit. The developed models consider non-ideal drift effects of the ISFETs. In addition, the proposed readout circuitry has been fabricated in a 0.35μm double-poly tetra-metal CMOS technology. The simulation results of the developed macromodel were compared with the experimental measurements. The modeled-versus-measured fit of the dependence of drift rate over an 18-hour period, pH range of 2~12 and temperature range of 5~35℃ present an RMS error of 2.2%, 2.4% and 6.6%, respectively. The proposed model and readout circuitry can be adopted for commercial ISFET-based pH meter applications.