Systematic errors in the calix  pyrrole-based potentiometric detection of creatinine have been observed in heavy smokers. This work further characterizes the interactions between the nicotinium cation and the cavitand as well as the resulting interference produced during the potentiometric detection. It is found that the nicotinium cation binds the electronic rich aromatic cavity defined by the pyrrole rings of the receptor’s cone conformation with an estimated binding constant higher than 10−4 M−1 in methylene chloride. On the other hand, the creatininium cation is preferentially included in the hydrophobic aromatic cavity of the ionophore by establishing hydrogen bond interactions with the pyrrole NHs groups. Potentiometric calibrations confirmed the detection of the nicotinium cation at neutral and acidic pH, respectively. Due to the lower pka of creatinine, a methodology to quantify creatinine in presence of nicotine by using an array of three sensors at two pH values is proposed. A partial least squares regression was performed and reported recoveries of 103% with a standard deviation of 20%. The improved determination of creatinine was therefore discussed. This approach represents a step forward in the development of effective approaches to improve the measurement of creatinine in decentralized settings.