       Document 0671
 DOCN  M9620671
 TI    pH-dependent oral absorption of L-735,524, a potent HIV protease
       inhibitor, in rats and dogs.
 DT    9602
 AU    Lin JH; Chen IW; Vastag KJ; Ostovic D; Merck Research Laboratories, West
       Point, PA 19486, USA.
 SO    Drug Metab Dispos. 1995 Jul;23(7):730-5. Unique Identifier : AIDSLINE
       MED/96089976
 AB    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)
 DE    Administration, Oral  Animal  Citrates/CHEMISTRY  Dogs  Hydrogen-Ion
       Concentration  HIV Protease Inhibitors/BLOOD/CHEMISTRY/*PHARMACOKINETICS
       Intestinal Absorption  Liver/METABOLISM  Male
       Methylcellulose/PHARMACOLOGY
       Pyridines/BLOOD/CHEMISTRY/*PHARMACOKINETICS  Rats  Rats, Sprague-Dawley
       Solubility  Species Specificity  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

