Cundy K C, Sue I L, Visor G C, Marshburn J, Nakamura C, Lee W A, Shaw J P
Gilead Sciences, Inc., Foster City, CA 94404, USA.
J Pharm Sci. 1997 Dec;86(12):1334-8. doi: 10.1021/js970264s.
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.
在比格犬中研究了剂型对前药阿德福韦酯中抗病毒核苷酸类似物阿德福韦口服生物利用度的影响。将阿德福韦酯颗粒的混悬液制剂给予五只禁食的雄性比格犬（每只犬250mg前药；每只犬相当于135.7mg阿德福韦）。由相同制粒（批次B94）制备的片剂以每只犬2×125mg前药的剂量给药。此外，将相同的片剂给予处于进食状态或经五肽胃泌素预处理后的犬。另外两个剂型稍有变化的片剂批次（H94和D501）也在经五肽胃泌素预处理的犬（n = 5）中进行了评估。血浆中阿德福韦的浓度通过荧光衍生化后的HPLC测定。在pH 2.0条件下检查片剂的溶出度。一批阿德福韦酯片剂在体外的溶出速率慢5倍（B94 = H94 >> D501）。阿德福韦酯在犬口服吸收后完全转化为阿德福韦。混悬液中阿德福韦的口服生物利用度为35.0±8.9%。片剂剂型中阿德福韦的口服生物利用度在禁食犬、进食犬和经五肽胃泌素预处理的禁食犬中分别为34.7±10.3%、37.2±4.5%和44.9±5.9%。所有三个片剂批次在犬中的生物利用度相当。前药中阿德福韦在犬中的口服生物利用度（35 - 46%）不受剂型、食物或胃肠道酸性pH的影响。阿德福韦酯片剂的体外溶出度与口服生物利用度无关。阿德福韦酯的口服生物利用度似乎受前药低渗透性和向阿德福韦的生物转化的限制。
