Lee, Jihye Kim, Bongchan Kim, Tae Hun Lee, Sun Hwa Park, Hee Dong Chung, Kyungha Lee, Sung-Hack Paek, Seungyup Kim, Eunice EunKyeong Yoon, SukKyoon Kim, Aeri 2024-01-20T04:32:46Z 2024-01-20T04:32:46Z 2021-09-05 2016-04 1543-8384 https://pubs.kist.re.kr/handle/201004/124233 LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their. solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin K-i, values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect. English AMER CHEMICAL SOC FACTOR XA PHARMACOKINETICS LB30870 PHARMACODYNAMICS A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It Article 10.1021/acs.molpharmaceut.5b00637 1 MOLECULAR PHARMACEUTICS, v.13, no.4, pp.1197 - 1205 MOLECULAR PHARMACEUTICS 13 4 1197 1205 scie scopus 000373550600001 2-s2.0-84963852954 Medicine, Research & Experimental Pharmacology & Pharmacy Research & Experimental Medicine Pharmacology & Pharmacy Article FACTOR XA PHARMACOKINETICS LB30870 PHARMACODYNAMICS trypsin cocrystal anticoagulant food effect screening dietary fiber