title: pH-dependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs.
abstract: 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, > 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 approximately 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 H2-receptor antagonist. L-735,524 underwent an extensive first-pass metabolism in rats, but not in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: K J
authors.initials: KJ
authors.lastname: Vastag
authors.forename: D
authors.initials: D
authors.lastname: Ostovic
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002951:Citrates / Q000737:chemistry; D019343:Citric Acid; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D019469:Indinavir; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D008747:Methylcellulose / Q000494:pharmacology; D011725:Pyridines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013045:Species Specificity
chemical_list: D002951:Citrates; D017320:HIV Protease Inhibitors; D011725:Pyridines; D019343:Citric Acid; D019469:Indinavir; D008747:Methylcellulose