Disposition and chemical stability of telmisartan 1-O-acylglucuronide

Telmisartan 1-O-acylglucuronide, the principal metabolite of telmisartan in humans, was characterized in terms of chemical stability and the structure of its isomerization products was elucidated. In addition, pharmacokinetic s of telmisartan 1-O-acylglucuronide were assessed in rats after i.v. dosin g. Similar to other acylglucuronides, telmisartan 1-O-acylglucuronide and d iclofenac 1-O-acylglucuronide, which was used for comparison, showed the fo rmation of different isomeric acylglucuronides on incubation in aqueous buf fer. The isomeric acylglucuronides of telmisartan consisted of the 2-O-, 3- O-, and 4-O-acylglucuronides (alpha,beta-anomers). First order degradation half-lives of 26 and 0.5 h were observed on incubation in buffer of pH 7.4 for the 1-O-acylglucuronides of telmisartan and diclofenac, respectively. T his indicated that the 1-O-acylglucuronide of telmisartan was among the mos t stable acylglucuronides reported to date. The high stability of telmisart an 1-O-acylglucuronide was confirmed by in vitro experiments that indicated only very low covalent binding of telmisartan acylglucuronide to human ser um albumin but a considerable amount of covalently bound radioactivity with the acylglucuronide of diclofenac. After i.v. dosing to rats, telmisartan 1-O-acylglucuronide was rapidly cleared from plasma with a clearance of 180 ml/min/kg, compared with 15.6 ml/min/kg for the parent compound. Because t elmisartan 1-O-acylglucuronide exhibited a comparably high chemical stabili ty together with a high clearance that resulted in low systemic exposure, t he amount of covalent binding to proteins should be negligible compared wit h other frequently used drugs, such as furosemide, ibuprofen, or salicylic acid.