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Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
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2008 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, nr 19, s. 5932-5942Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

Ort, förlag, år, upplaga, sidor
2008. Vol. 51, nr 19, s. 5932-5942
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-86815DOI: 10.1021/jm8003152ISI: 000259760500010PubMedID: 18788725OAI: oai:DiVA.org:uu-86815DiVA, id: diva2:127485
Tillgänglig från: 2008-12-08 Skapad: 2008-12-08 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. In vitro and in silico prediction of drug-drug interactions with transport proteins
Öppna denna publikation i ny flik eller fönster >>In vitro and in silico prediction of drug-drug interactions with transport proteins
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities.

The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined.

The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins.

The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed.

In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2009. s. 65
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 104
Nyckelord
Solute carrier, SLC transporter, OCT1, Organic cation transporter 1, SLC22A1, OATP1B1, SLCO1B1, Organic anion transporting peptide 1B1, Drug transport, Active transport, Genetic polymorphism, Cell lines, Gene expression, Multivariate data analysis, OPLS
Nationell ämneskategori
Farmaceutiska vetenskaper Farmaceutiska vetenskaper
Forskningsämne
galenisk farmaci; biofarmaci
Identifikatorer
urn:nbn:se:uu:diva-107492 (URN)978-91-554-7589-5 (ISBN)
Disputation
2009-10-02, B21, Biomedical Center, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-09-10 Skapad: 2009-08-13 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Larsson, RolfBergström, Christel A S

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