Indinavir: A Rare Urinary Stone in HIV-1-Infected Patients Occurrence and Crystal Properties

摘要

The treatment of the human immunodeficiency virus (HIV) infection has been extremely improved by the introduction of a new class of anti-HIV-drugs, the protease inhibitors [1]. Indinavir is one of these protease inhibitors, recently introduced as combination therapy in HIV-1-positive patients [2]. The badly soluble compound is formulated as the sulphate salt in capsules for oral administration (Crixivan, registered trademark of Merck & Co., Inc., 1996). One of the most significant side effects of this drug is the formation of urinary stones with an incidence of about 4% [3, 4]. However, recent studies report frequencies of 12% [5] or even 43% [6] and thus the overall prevalence of indinavir nephrolithiasis is estimated to be much higher than the 4% stated in the manufacturers product insert. The reason for the formation of urinary stones is attributed to the pH-dependent solubility of indinavir. The solubility in water at a pH < 3.5 exceeds 100 mg·mL{sup}(-1) [7] and drops to about 0.02 mg·mL{sup}(-1) at pH values of 7.0 [3], which means that a 5000 fold decrease in solubility occurs between the application site (indinavir sulphate dissolved in stomach fluid) and the blood plasma (pH 7.4) respectively the urine (pH 6.7 to 7.4). The indinavir concentration in the urine right after the glomerular filtration in the kidney is near the limits of solubility and due to the following reabsorption of water the urine becomes increasingly concentrated and finally supersaturated in the kidney (particularly in the loop of Henle). Under the pH and ionic strength conditions applying to a certain section in the kidney it was found that indinavir crystallizes even at a concentration of 0.008 mg·mL{sup}(-1) [8].