Influence of body temperature on indinavir crystallization under loop of Henle conditions

Indinavir is a protease inhibitor used in the therapy of HIV-1+ patients. It causes indinavir stone formation. It has been shown to precipitate in the loop of Henle (LH) at plasma concentrations (conc[P]) of approximately 8 mg/L. Those experiments were performed at room temperature. Given the influence of temperature on crystallization in general, and solubility of indinavir in particular, we repeated the experiments under physiological (body) temperature conditions.

Test solutions contained indinavir concentrations of 100-750 mg/L at ionic strengths varying from 0 to 800 mM simulating conditions in the proximal tubule and the LH. Solutions were titrated with base (NaOH) to find the pH value where nucleation is initiated. Experiments were conducted at room temperature (20 degrees C) and repeated under constantly monitored (body) temperature (37 degrees C).

Experiments at 20 degrees C confirmed our previous results. At 37 degrees C, the relationship between pH and indinavir concentration remained inversely proportional. Again, the LH was confirmed as the most likely localization of crystallization. However, at 37 degrees C precipitation occurred at a lower urinary concentration (100 versus 125 mg/L) and within a lower pH range (6.67-7.26 versus 7.23-7.44). This lower urinary concentration corresponds to a lower conc[P] [critical value (CV)] of 6.41 mg/L, as compared with 8.01 mg/L at 20 degrees C.

The CV is even lower at 37 degrees C than previously assumed. Plasma peak concentration above the CV of 6.4 mg/L will induce crystallization in the LH and should be avoided.