Reid Joel M, Mandrekar Sumithra J, Carlson Elsa C, Harmsen W Scott, Green Erin M, McGovern Renee M, Szabo Eva, Ames Matthew M, Boring Daniel, Limburg Paul J
Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Cancer Epidemiol Biomarkers Prev. 2008 Mar;17(3):674-9. doi: 10.1158/1055-9965.EPI-07-2510.
The cyclooxygenase (COX)-2 enzyme appears to be an important target for cancer chemoprevention. Given the recent emergence of potentially serious cardiovascular toxicity associated with selective COX-2 inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2, have received renewed attention as candidate chemoprevention agents. Sulindac has shown consistent chemopreventive potential in preclinical studies as well as in a limited number of clinical trials reported to date. For the current pharmacokinetic study, sulindac capsules were prepared to facilitate ample agent supplies for future intervention studies. Encapsulation of the parent compound (sulindac sulfoxide) can be readily accomplished, but the effects of alternate formulations on bioavailability have not been rigorously examined. In the present single-dose, two-period crossover trial, we conducted pharmacokinetic analyses of sulindac in capsule (test) versus tablet (reference) formulations. Overall, bioavailability appeared to be higher for the capsule compared with the tablet formulation based on test-to-reference pharmacokinetic variable ratios for the parent compound alone. However, additional analyses based on the sulfide and sulfone metabolites of sulindac with the same pharmacokinetic variables indicated similar chemopreventive exposures between the capsule and tablet formulations. These data support the use of sulindac capsules, which can be readily prepared with matching placebos, in future blinded chemoprevention trials.
环氧化酶（COX）-2 似乎是癌症化学预防的一个重要靶点。鉴于近期与选择性 COX-2 抑制剂相关的潜在严重心血管毒性的出现，抑制 COX-1 和 COX-2 的非甾体抗炎药（NSAIDs）作为候选化学预防药物再次受到关注。舒林酸在临床前研究以及迄今为止报道的有限数量的临床试验中均显示出一致的化学预防潜力。在本次药代动力学研究中，制备了舒林酸胶囊，以为未来的干预研究提供充足的药物供应。母体化合物（舒林酸亚砜）的胶囊化很容易实现，但替代剂型对生物利用度的影响尚未得到严格研究。在本次单剂量、两期交叉试验中，我们对舒林酸胶囊（试验）与片剂（对照）剂型进行了药代动力学分析。总体而言，仅基于母体化合物的试验与对照药代动力学变量比率，胶囊剂型的生物利用度似乎高于片剂剂型。然而，基于舒林酸的硫化物和砜代谢物以及相同药代动力学变量的进一步分析表明，胶囊和片剂剂型之间的化学预防暴露相似。这些数据支持在未来的盲法化学预防试验中使用舒林酸胶囊，其可以很容易地与匹配的安慰剂一起制备。
