In vitro data has limitations and may not reflect what occurs in the whole organism. The conversion rate may be slower or faster, the concentrations different, etc., which is why it is not always possible to follow the entire bioconversion in vivo. The three compounds, aripiprazole, N-hydroxymethyl aripiprazole and aripiprazole lauroxil, were therefore dosed intravenously to three different groups of rats. The plasma concentration time profile following administration of aripiprazole

can be seen in Fig. 4A. The profile could be described by a bi-exponential equation: equation(3) Cpl=1464⋅e−2.77t+1205⋅e−0.16tCpl=1464⋅e−2.77t+1205⋅e−0.16t where Cpl is the concentration of aripiprazole (nanomol) in plasma and t is time (in hours). The AUC0→∞ was 8176 ± 2647 nmol h/L, clearance 1.37 ± 0.61 L/h/kg and volume of distribution 8.16 ± 0.75 L/kg giving a terminal plasma half-life of ≈4.2 h. This is slightly longer than that previously INCB024360 cost reported following non-compartmental evaluation after p.o. dosing in male Sprague Dawley rats [ 46]. The plasma concentration-time

profile after injection of N-hydroxymethyl aripiprazole into rats is presented in Fig. 4B together with the concentration of aripiprazole measured during the bioconversion of N-hydroxymethyl aripiprazole. The plasma concentration curve had a similar profile for both compounds. The bioconversion from N-hydroxymethyl aripiprazole did not seem to be rate limiting for the formation of aripiprazole. This supports the findings of the in vitro VE-822 datasheet study. Analysis of the emulsion just after dosing showed formation of aripiprazole (i.e., the exact pharmacokinetic parameters for N-hydroxymethyl aripiprazole and aripiprazole) cannot be described by this experiment.

This highlights nearly some of the scientific problems when investigating these bioconversions. The intention was to stabilise the compound through incorporation into a dispersed system, but hydrolysis was still observed. Developing methods and procedures for the evaluation of these intermediates is thus difficult and may in part explain the lack of in vivo investigations of prodrug conversion in the literature. However, from a drug development and patient safety point of view, it is a critical parameter to consider. The plasma concentration–time profile after the injection of aripiprazole lauroxil into rats is shown in Fig. 4C, together with the amounts of N-hydroxymethyl aripiprazole and aripiprazole formed as a result of the bioconversion of the prodrug. No degradation of aripiprazole lauroxil was observed in the formulation, i.e., aripiprazole lauroxil was sufficiently stable to allow a pharmacokinetic evaluation of the compound. The clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg. Interestingly, all three compounds were detected in the animals, demonstrating that the suggested biological conversion scheme presented in Fig.