       Document 0503
 DOCN  M9630503
 TI    Species dependent esterase activities for hydrolysis of an anti-HIV
       prodrug glycovir and bioavailability of active SC-48334.
 DT    9603
 AU    Cook CS; Karabatsos PJ; Schoenhard GL; Karim A; Department of Clinical
       Pharmacology, Searle Research and; Development, Skokie, Illinois 60077,
       USA.
 SO    Pharm Res. 1995 Aug;12(8):1158-64. Unique Identifier : AIDSLINE
       MED/96021491
 AB    PURPOSE. The in vitro fate of an ester prodrug, glycovir, was studied to
       determine if the species differences in the bioavailability of
       pharmacologically active SC-48334 observed after glycovir administration
       and not observed after SC-48334 administration is due to species
       differences in ester hydrolysis rate or species differences in
       absorption of the prodrug itself, and to determine the site(s) of ester
       hydrolysis which contributes most to species differences in the
       bioavailability of SC-48334 if any. METHODS. Glycovir was incubated with
       small intestinal mucosa, liver S9 fractions, whole blood, red blood
       cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus)
       and man, and glycovir concentrations were determined by HPLC. RESULTS.
       The relative bioavailabilities of SC-48334 after prodrug administration
       to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively.
       After SC-48334 administration, SC-48334 was rapidly and similarly well
       absorbed in all species. The hydrolysis rate in the small intestinal
       mucosa was well correlated with the relative bioavailability of SC-48334
       after prodrug administration. Among different species the hydrolysis
       rate of glycovir in liver S9 fractions, blood, RBC and plasma did not
       parallel those in the mucosa of the small intestine. CONCLUSIONS. The
       species differences in bioavailability of SC-48334 with the prodrug were
       due to species differences in hydrolysis rates of the prodrug in small
       intestinal mucosa. The monkey was a good animal model for prediction of
       esterase activity in human small intestine and relative bioavailability
       in man.
 DE    Adolescence  Adult  Animal  Antiviral Agents/BLOOD/*PHARMACOKINETICS
       Biological Availability  Butyrates/BLOOD/*PHARMACOKINETICS  Comparative
       Study  Dogs  Esterases/*METABOLISM  Female  Human  Hydrolysis  HIV/*DRUG
       EFFECTS  HIV Seropositivity/METABOLISM  In Vitro  Intestinal Absorption
       Intestinal Mucosa/METABOLISM  Liver/METABOLISM  Macaca fascicularis
       Male  Piperidines/BLOOD/*PHARMACOKINETICS  Prodrugs/*PHARMACOKINETICS
       Rats  Species Specificity  Subcellular Fractions/METABOLISM
       1-Deoxynojirimycin/*ANALOGS & DERIVATIVES/BLOOD/PHARMACOKINETICS
       CLINICAL TRIAL  JOURNAL ARTICLE

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

