Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3’R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues

Abstract The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2 R 3’ R -SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2 R 3’ R -SGM was metabolized to 2 R 3’ R -SGa in plasma but was stable in liver and intestine. The half-life of 2 R 3’ R -SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2 R 3’ R -SGM in humans and rats. The PON1-mediated hydrolysis of 2 R 3’ R -SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2 R 3’ R -SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2 R 3’ R -SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2 R 3’ R -SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study.