This work strived to explore gastrointestinal (GI) dissolution, supersaturation and precipitation of the weakly basic drug atazanavir in humans under different 'real-life' intake conditions. The impact of GI pH and motility on these processes was thoroughly explored. In a cross-over study, atazanavir (Reyataz®) was orally administered to 5 healthy subjects with (i) a glass of water, (ii) a glass of Coca-Cola® and (iii) a glass of water under hypochlorhydric conditions (induced by concomitant intake of a proton-pump inhibitor (PPI)). After intake, GI fluids were aspirated from the stomach and the duodenum and, subsequently, analyzed for atazanavir. In parallel, blood samples were collected to assess systemic concentrations. In general, the results of this study revealed that the acidic gastric pH in combination with gastric residence time played a crucial role in the dissolution of atazanavir along the GI tract. After intake of atazanavir with a glass of water (i.e., reference condition), complete gastric dissolution was observed. After GI transfer, supersaturation was noticed for a limited amount of time (1.25 h). With respect to the Coca-Cola® condition, complete gastric dissolution was also observed. A delay in gastric emptying, highly likely caused by the caloric content (101 kcal), was responsible for delayed arrival of atazanavir into the upper small intestine, creating a longer time window of supersaturated concentrations in the duodenal segment (3.25 h) compared to the water condition. The longer period of supersaturated concentrations resulted in a slightly higher systemic exposure of atazanavir compared to the condition when atazanavir was taken with a glass of water. A remarkable observation was the creation (when the drug was given in the migrating motor complex (MMC) phase 2) or maintenance (when the drug was given in MMC phase 1) of a quiescent phase for up to 80 min. With respect to the PPI condition, negligible gastric and intestinal concentrations were observed, resulting in minimal systemic exposure for all subjects. It can be concluded that gastric pH and residence time play a pivotal role in the intestinal disposition of atazanavir in order to generate sufficiently high concentrations further down in the intestinal tract for a sufficient period of time, thus creating a beneficial driving force for intestinal absorption.

中文翻译：

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探索实际给药条件对健康受试者胃动记录与阿扎那韦并行的腔内和全身浓度的影响。

这项工作致力于探索弱碱性药物阿扎那韦在不同“现实”摄入条件下在人体内的胃肠道（GI）溶解，过饱和和沉淀。彻底探讨了胃肠道pH和运动性对这些过程的影响。在一项交叉研究中，向（a）一杯水，（ii）一杯可口可乐和（iii）在低氯水条件下的一杯水对5位健康受试者口服阿扎那韦（Reyataz®）（伴随摄取质子泵抑制剂（PPI）引起的。摄入后，从胃和十二指肠抽吸胃肠液，然后分析阿扎那韦。同时，收集血液样本以评估全身浓度。一般来说，这项研究的结果表明，酸性胃液pH值与胃液停留时间的结合在阿扎那韦沿胃肠道的溶解中起着至关重要的作用。用一杯水摄入阿扎那韦后（即参考状态），观察到胃完全溶解。胃肠道转移后，在有限的时间（1.25小时）内观察到过饱和。关于可口可乐的状况，还观察到胃完全溶解。胃排空的延迟很可能是由热量含量（101 kcal）引起的，这是造成阿扎那韦延迟进入小肠上部的原因，与十二指肠段相比，在十二指肠段（3.25 h）产生了更长的过饱和浓度时间窗水状况。与用一杯水服用阿扎那韦的情况相比，较长时间的过饱和浓度导致阿扎那韦的全身暴露量稍高。一个显着的观察结果是静态阶段的创建（当药物在迁移运动复合物（MMC）第2阶段给药时）或维持（当药物在MMC阶段1给药时）静止期长达80分钟。关于PPI状况，观察到的胃和肠浓度可忽略不计，因此所有受试者的全身暴露量均降至最低。可以得出结论，胃酸pH值和停留时间在阿扎那韦的肠道处置中起着关键作用，以便在足够长的时间内在肠道内进一步产生足够高的浓度，