Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Australian Synchrotron, ANSTO, 800 Blackburn Road, Clayton, Victoria 3168, Australia.
Mol Pharm. 2023 Apr 3;20(4):2256-2265. doi: 10.1021/acs.molpharmaceut.3c00072. Epub 2023 Mar 14.
The development of formulation approaches to coadminister lopinavir and ritonavir antiretroviral drugs to children is necessary to ensure optimal treatment of human immunodeficiency virus (HIV) infection. It was previously shown that milk-based lipid formulations show promise as vehicles to deliver antimalarial drugs by enhancing their solubilization during the digestion of the milk lipids under intestinal conditions. In this study, we investigate the role of digestion of milk and infant formula on the solubilization behavior of lopinavir and ritonavir to understand the fate of drugs in the gastrointestinal (GI) tract after oral administration. Small angle X-ray scattering (SAXS) was used to probe the presence of crystalline drugs in suspension during digestion. In particular, the impact of one drug on the solubilization of the other was elucidated to reveal potential drug-drug interactions in a drug combination therapy. Our results showed that lopinavir and ritonavir affected the solubilization of each other during digestion in lipid-based formulations. While addition of ritonavir to lopinavir improved the overall solubilization of lopinavir, the impact of lopinavir was to reduce ritonavir solubilization as digestion progressed. These findings highlight the importance of assessing the solubilization of individual drugs in a combined matrix in order to dictate the state of drugs available for subsequent absorption and metabolism. Enhancement in the solubilization of lopinavir and ritonavir in a drug combination setting also supported the potential for food effects on drug exposure.
开发联合应用洛匹那韦和利托那韦抗逆转录病毒药物的配方方法对于确保人类免疫缺陷病毒（HIV）感染的最佳治疗非常必要。此前有研究表明，基于乳脂的脂质配方可作为载体，通过增强肠道条件下消化乳脂时抗疟药物的溶解来提高其溶解度。在这项研究中，我们研究了消化乳和婴儿配方对洛匹那韦和利托那韦溶解行为的影响，以了解口服给药后药物在胃肠道（GI）中的命运。小角 X 射线散射（SAXS）用于探测悬浮液中结晶药物在消化过程中的存在。特别地，阐明了一种药物对另一种药物溶解的影响，以揭示药物组合疗法中潜在的药物相互作用。我们的研究结果表明，洛匹那韦和利托那韦在基于脂质的配方中消化时会影响彼此的溶解。虽然在洛匹那韦中添加利托那韦可提高洛匹那韦的总体溶解度，但随着消化的进行，洛匹那韦的作用是降低利托那韦的溶解度。这些发现强调了在组合基质中评估各药物溶解情况的重要性，以决定随后吸收和代谢的药物状态。在药物联合应用中，洛匹那韦和利托那韦的溶解增强也支持了食物对药物暴露的影响。
