Using the prodrug principle as a means of life cycle management is, therefore, not simple from a scientific, a developmental or a regulatory point of view and requires significant

cross-functional efforts to succeed. However, if the benefit is clinical significant for the patient, it could be a potential enabling approach, for example, for a defined route of administration. Aripiprazole is approved as an effective treatment for various psychiatric disorders [[20], [21], [22] and [23]]. The compound is marketed in several dosage formulations, including tablets, orally disintegrating tablets, an oral solution, and as a suspension for once-monthly intramuscular injection Selleck ABT 263 as a depot. Recently an N-acyloxymethyl selleck inhibitor prodrug of aripiprazole (aripiprazole lauroxil) intended for intramuscular injection has been described [ 24]. Bioconversion of N-acyloxyalkyl derivatives of NH-acidic compounds is thought

to proceed through a hydrolytical two step process as previously investigated and thoroughly described by Hans Bundgaard and coworkers e.g. [ [25], [26], [27], [28], [29], [30] and [31]], as illustrated for aripiprazole lauroxil in Fig. 1. The rate of prodrug conversion of N-acyloxymethyl derivatives of NH-acidic compounds is firstly determined by the rate of enzymatic or non-enzymatic catalysed hydrolysis of the ester bond into the corresponding carboxylic acid and N-hydroxyalkyl moieties followed by a non-enzymatic spontaneous cleavage into the parent drug molecule and an aldehyde, e.g. formaldehyde as in

the case of aripiprazole lauroxil. The later process is thought to be solely dependent on pH and temperature as previously described [ 25, [30], [31] and [32]]. To the best of our knowledge, no information is available on the conversion of N-acyloxyalkyl derivates of NH-acidic compounds focusing Docetaxel in vivo on simultaneous quantification of all components and intermediates in the two step bioconversion, i.e., the prodrug, the N-hydroxyalkyl intermediate and the parent NH-acidic compound, both in vitro and in vivo. Thus, in the present study, we use aripiprazole lauroxil as a model compound for an N-acyloxyakyl prodrug of an N-acidic compound (drug) to provide an insight into the biological conversion of these compounds. Aripiprazole was obtained from Otsuka pharmaceutics (Tokyo, Japan), while N-hydroxymethyl-aripiprazole and aripiprazole lauroxil were synthesised as described below. Reagents and solvents for the synthetic work were obtained from Sigma-Aldrich (St.