pH-dependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs
Lin, J.H.; Chen, I.W.; Vastag, K.J.; Ostovic, D.
Drug Metabolism and Disposition the Biological Fate of Chemicals 23(7): 730-735
1995
ISSN/ISBN: 0090-9556 PMID: 7587962 Document Number: 450319
L-735,524, a potent and specific inhibitor of human immunodeficiency virus protease, is currently under investigation for the treatment of acquired immunodeficiency syndrome. The aqueous solubility of L-735,524 was pH-dependent, gt 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 apprx 16% for both dogs and rats. When the same dose of the drug was administered in 0.05 M citric acid (pH 2.5), the bioavailability increased 4.5-fold in dogs (72%), but only slightly in rats (24%). The pH- and species-dependent differences in bioavailability observed in rats and dogs may be because of differences in the rate of gastric acid secretion and in the magnitude of hepatic first-pass effect. Gastric acid secretion is poor in dogs but substantial in rats. When L-735,524 was administered in 0.5% methocel, 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 substantially decreased in rats after pretreatment with famotidine, a potent H-2-receptor antagonist. L-735,524 underwent an extensive first-pass metabolism in rats, but not in dogs. The hepatic first-pass extraction in rats was estimated to be apprx 70% by comparing the steady-state drug concentrations during portal and femoral vein infusions. Thus, the low bioavailability of L-735,524 observed in rats was mainly caused by an extensive first-pass effect.