There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxy-carbonyloxymethyl) PMPA 8 (t1/2 < 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.

The pharmacokinetics, bioavailability, and metabolism of the anti-human immunodeficiency virus nucleotide analog 9[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) were determined in beagle dogs following intravenous, intraperitoneal, and oral administration. Fasted male beagle dogs (n ‫؍‬ 5) were pretreated with pentagastrin and received PMPA (10 mg/kg of body weight) by the intravenous and oral routes with a washout period of 1 week between doses. A further group of male dogs received PMPA as a single dose via the intravenous (1 mg/kg; n ‫؍‬ 5) and the intraperitoneal (10 mg/kg; n ‫؍‬ 3) routes, with 1-week washout period between doses. The concentrations of PMPA in plasma and urine were determined over 48 h postdosing by fluorescence derivatization and high-performance liquid chromatography (HPLC). The potential for metabolism or biliary excretion of PMPA was evaluated in a dog with a chronic indwelling bile cannula. Urine, feces, and bile were collected at intervals over 48 h following the intravenous administration of [ 14 C]PMPA (10 mg/kg; 55 Ci/kg). The concentrations of PMPA in plasma after intravenous injection were best described by an open two-com-partment model with a terminal half-life of approximately 10 h. PMPA was excreted unchanged in urine (70%); recovery in feces (0.42%) or bile (0.26%) was negligible. The plasma clearance of PMPA (0.28 ؎ 0.05 liter/h/kg) was substantially greater than the glomerular filtration rate in this species, suggesting active tubular secretion of PMPA. No metabolites of [ 14 C]PMPA were observed in urine, feces, or bile on the basis of HPLC with radioactive flow detection. The remainder of the dose was probably excreted unchanged in urine beyond 48 h postdosing. The mean ؎ standard deviation observed bioavailabilities of PMPA following oral and intraperitoneal administration at 10 mg/kg were 17.1% ؎ 1.88% and 73.5% ؎ 10.5%, respectively. MATERIALS AND METHODS Materials. PMPA monohydrate and adefovir were obtained from Gilead Sciences, Inc. (Foster City, Calif.). [8-14 C]PMPA (lot 117-303-026; specific activity, 26 mCi/mmol) was obtained as a solution in ethanol-water (70:30) from Moravek (Brea, Calif.). There were no detectable impurities in the radioactive material on the basis of high-performance liquid chromatography (HPLC) with radioactive flow detection. Pentagastrin (Peptavlon; 0.25 mg/ml) was obtained from Ayerst Laboratories, Inc. (Philadelphia, Pa.). Tetrabutylammonium dihydrogen phosphate (TBAHP) was obtained from Fluka (Ronkonkoma, N.Y.). Acetonitrile was from Burdick and Jackson (Muskegon, Mich.). Chloroacetaldehyde and trifluoroacetic acid were from Aldrich (Milwaukee, Wis.). All other chemicals were from Mallinckrodt (Phillipsburg, N.J.).Formulations. Unlabelled PMPA monohydrate was formulated for intravenous or intraperitoneal administration as a sterile aqueous solution in water for injections, and the solution was adjusted to pH 7.4 with 1 N sodium hydroxide. Solutions containing 5 and 50 mg of PMPA/ml were prepared and were sterilized by filtration with a...

A series of 15-mer oligodeoxynucleotide analogues were synthesized, and their thrombin inhibitory activities in vitro and in vivo were evaluated. These oligodeoxynucleotide analogues share the same sequence (GGTTGGTGTGGTTGG) but have one or more phosphodiester linkages replaced by a neutral formacetal group. The results obtained from monosubstitutions show that no single phosphodiester group is critical for the thrombin inhibitory activity, suggesting that the interaction between the oligodeoxynucleotide and thrombin is based on a multiple-site charge-charge interaction. Analysis of the effects of different phosphodiester replacements indicates that the backside and left side of the chairlike structure formed by the molecule may be involved in binding with thrombin, presumably by having direct contacts with the anion-binding exosite of the enzyme. For the oligodeoxynucleotides containing two noncontiguous formacetal groups, the effect of the disubstitution is the sum of the effects obtained from the corresponding two monosubstitutions. Infusion of an oligodeoxynucleotide containing four formacetal groups into monkeys showed an increased in vivo anticoagulant effect and an extended in vivo half-life compared to the unmodified oligodeoxynucleotide.