Oral Formulations of Adefovir Dipivoxil: In Vitro Dissolution and in Vivo Bioavailability in Dogs
| Autor: | I-Lan Sue, Gary C. Visor, Jane Marshburn, Kenneth C. Cundy, Carey Nakamura, Jeng-Pyng Shaw, William A. Lee |
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| Rok vydání: | 1997 |
| Předmět: |
Male
Organophosphonates Administration Oral Biological Availability Pharmaceutical Science Pharmacology Antiviral Agents Beagle Dosage form Food-Drug Interactions Dogs Pharmacokinetics Oral administration medicine Adefovir Animals Chemistry Adenine virus diseases Fasting Hydrogen-Ion Concentration Prodrug digestive system diseases Bioavailability Pentagastrin Solubility Injections Intravenous Tablets medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 86:1334-1338 |
| ISSN: | 0022-3549 |
| DOI: | 10.1021/js970264s |
| Popis: | The effect of formulation on oral bioavailability of the antiviral nucleotide analogue adefovir from the prodrug adefovir dipivoxil was examined in beagle dogs. A suspension formulation of adefovir dipivoxil granules was administered to five fasted male beagle dogs (250 mg prodrug per dog; 135.7 mg-equiv of adefovir per dog). Tablets prepared from the same granulation (batch B94) were administered at 2 x 125 mg prodrug per dog. In addition, the same tablets were administered to dogs in the fed state or following pentagastrin pretreatment. Two further tablet batches (H94 and D501) with slight formulation changes were also evaluated in pentagastrin pretreated dogs (n = 5). Concentrations of adefovir in plasma were determined by HPLC following fluorescence derivatization. Tablet dissolution was examined at pH 2.0. One batch of adefovir dipivoxil tablets showed a 5-fold slower dissolution rate in vitro (B94 = H94 >> D501). Adefovir dipivoxil was completely converted to adefovir following oral absorption in dogs. The oral bioavailability of adefovir from the suspension was 35.0 +/- 8.9%. The oral bioavailability of adefovir from the tablet formulation was 34.7 +/- 10.3%, 37.2 +/- 4.5%, and 44.9 +/- 5.9% in fasted dogs, fed dogs and fasted dogs pretreated with pentagastrin, respectively. All three tablet batches had equivalent bioavailability in dogs. Oral bioavailability of adefovir from the prodrug in dogs (35-46%) was unaffected by formulation, food, or the acidic pH of the gastrointestinal tract. In vitro dissolution of adefovir dipivoxil tablets did not correlate with oral bioavailability. Oral bioavailability of adefovir dipivoxil appears to be limited by low permeability and biological conversion of the prodrug to adefovir. |
| Databáze: | OpenAIRE |
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