Abstracts Category : Other

pH oscillations and bistability predicted by a model of a trizenzymatic system that produces an anti-depressant

by Zhiheng Wang

A controlled drug delivery system is typically designed to deliver the drug at a controlled rate; its benefits including improve patients??? compliance compare to traditional formulations as well as not disrupting circadian rhythms if set on a 24-hour period. Some delivery systems exhibit the potential of producing drug in-situ without pre-loading the drug. Because of the availability of methylated creatine in human muscle, we use creatine-creatinase system as the source of an anti-depressant sarcosine. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It can enhance glycine concentration around NMDA receptors; as a result, modulates glutamatergic transmission function, which is usually found impaired in patients with depressant and schizophrenia. Here we aim to establish the basis for a pH Sensitive Drug Delivery System (PSDDS) with characteristics of both biocompatibility and rhythmic delivery of the antidepressant. The system will have an enzymatic network as building block which is capable of inducing pH oscillations and sarcosine production. In this work, we carry out numerical simulations using a model based on the kinetics of the enzymatic reactions. The results of the simulations generate sets of the initial conditions necessary for the system to produce the rhythmic behavior mentioned above. Our enzymatic network is composed of creatinase-urease-sarcosine oxidase. Urea produced by substrate- enzyme creatine-creatinase will be hydrolyzed by urease to produce ammonia which participates in the pH oscillation. Furthermore, the concentration of sarcosine is controlled by the addition of sarcosine oxidase. Our results show that pH oscillations with a pH variation of 5 units are obtained by introducing an inhibitory effect on the enzyme urease. Urease inhibition adds a negative feedback which depends on the concentration of OH???. We also found that the magnitude of the pH variation is related to the concentration of the enzymes and substrates added to the reaction through of a constant influx.