Naslov
The throughput challenges in ADME investigation of IBD drugs and nutrients using liquid chromatography and in silico methodologies

Autori
Mornar, Ana ; Brusač, Edvin ; Amidžić Klarić, Daniela ; Nigović, Biljana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, prošireni sažetak, znanstveni

Izvornik
18th International Chromatography School / Ašperger, Daniela ; Ukić, Šime - Zagreb : Fakultet kemijskog inženjerstva i tehnologije Sveučilišta u Zagrebu, 2018, 19-20

ISBN
978-953-6470-85-3

Skup
18th International Chromatography School

Mjesto i datum
Zagreb, Hrvatska, 14.06.2018. - 15.06.2018

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
IBD, ADME, in silico, RP-HPLC, IAM-HPLC, HSA-HPLC

Sažetak
Crohn's disease and ulcerative colitis are two major forms of chronic inflammatory bowel disease (IBD). The etiology of inflammatory bowel disease is not fully clarified, but it is known to be an immune disorder in genetically predisposed individuals. Incidence of IBD is increasing worldwide, especially in developing countries and Asia. IBD has a peak incidence in both men and women aged between 20 and 35. Therefore, IBD usually affects women during their reproductive years and many concerns arise among these young patients. Treating IBD in pregnant women presents unique challenges. The key to a successful pregnancy of IBD patients is achieving and maintaining disease remission. If necessary, the safest drug possible should be used, with attention to the optimal efficacy for the patient’s condition. Regarding folic acid, special attention is given to the increased risk of malabsorption, as well as the effects of some drugs, such as sulfasalazine, on folate metabolism. The 2010 European Crohn’s and Colitis Organisation guidelines state that all IBD patients should be prescribed 1 mg folic acid daily in anticipation of pregnancy. Moreover, several studies have shown that some patients need to be on even higher doses of folic acid than the standard dose (5 mg/day). The fixed-dose combinations of IBD drugs and folic acid are not available on market. To give insight into compatibility of active pharmaceutical ingredients (APIs) in proposed fixed-dose combinations, investigation of their ADME properties is of exceptional importance1, 2. In this study ADME data of selected APIs obtained by two different high-throughput tools were compared. In silico ADME studies use various models developed for predicting ADME properties of compounds based on their chemical structures. Afterwards these properties are used to simulate pharmacokinetics of novel compounds. Sophisticated chromatographic columns obtained by immobilization of phospholipids and plasma proteins onto the surface of silica particles make liquid chromatography an attractive high- throughput technique in ADME investigation. ADME properties of IBD drugs and folic acid were predicted by 15 on-line available computer platforms. Furthermore, absorption and plasma protein binding of selected APIs were investigated by C18-HPLC, IAM-HPLC and HSA- HPLC. The logkw values obtained by C18-HPLC were in the range from 0.45 (6-mercaptopurine) to 1.34 (azathioprine), while logkw values obtained by IAM-HPLC were lower, from -0.37 (folic acid) to 0.68 (azathioprine). To evaluate plasma protein binding of APIs by HSA- HPLC technique the method was validated using literature plasma protein binding data3 (r=0.98). The lowest plasma protein binding was found for 6- mercaptopurine (20%), while the folic acid showed the longest retention time on the HSA- HPLC column and subsequently the highest plasma protein binding (69%) among the investigated compounds. Literature [1] Y. Kubota-Sjogren, K. Harding, P. Irving, C. Nelson-Piercy, Inflammatory bowel disease in pregnancy: management strategy based on best evidence and European guidelines, Brit J Gen Pract, 2014, 593-594. [2] K.M. De Felice, S.V. Kane, Inflammatory bowel disease in women of reproductive age, Expert Rev Gastroent, 2014, 417-425. [3] K. Valko, S. Nunhuck, C. Bevan, M.H. Abraham, D.P. Reynolds, Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity, J Pharm Sci, 2003, 2236-2248. Acknowledgment This work has been supported in part by the Croatian Science Foundation under the project number [UIP-2017-05-3949].

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

POVEZANOST RADA