PH-DEPENDENT ORAL ABSORPTION OF L-735,524, A POTENT HIV PROTEASE INHIBITOR, IN RATS AND DOGS

L-735,524, a potent and specific inhibitor of human immunodeficiency v irus protease, is currently under investigation for the treatment of a cquired immunodeficiency syndrome. The aqueous solubility of L-735,524 was pH-dependent, >100 mg/ml at pH below 3.5 and 0.03 mg/ml at pH 6. When L-735,524 was given orally as a suspension in 0.5% methocel (pH 6 .5) at 10 mg/kg, the bioavailability was similar to 16% for both dogs and rats. When the same dose of the drug was administered in 0.05 M ci tric acid (pH 2.5), the bioavailability increased 4.5-fold in dogs (72 %), but only slightly in rats (24%). The pH- and species-dependent dif ferences in bioavailability observed in rats and dogs may be because o f differences in the rate of gastric acid secretion and in the magnitu de of hepatic first-pass effect. Gastric acid secretion is poor in dog s but substantial in rats. When L-735,524 was administered in 0.5% met hoeel, a large portion of the drug in dogs, but not in rats, remained undissolved, resulting in poor absorption in dogs. On the other hand, when L-735,524 was administered in citric acid, most of the drug would be in solution allowing for better absorption in dogs. The hypothesis of pH-dependent absorption was further supported by the findings that absorption was significantly increased in dogs after feeding, but sub stantially decreased in rats after pretreatment with famotidine, a pot ent H-2-receptor antagonist. L-735,524 underwent an extensive first-pa ss metabolism in rats, but not in dogs, The hepatic first-pass extract ion in rats was estimated to be similar to 70% by comparing the steady -state drug concentrations during portal and femoral vein infusions. T hus, the low bioavailability of L-735,524 observed in rats was mainly caused by an extensive first-pass effect.