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Hepatic disposition of ximelagatran and its metabolites in pig; prediction of the impact of membrane transporters through a simple disposition model
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
Visa övriga samt affilieringar
2010 (Engelska)Ingår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, nr 4, s. 597-607Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose: The double prodrug ximelagatran is bioconverted, via the intermediates ethylmelagatran and N-hydroxymelagatran, to the direct thrombin inhibitor melagatran. The aims of this study were 1) to investigate the hepatic metabolism and disposition of ximelagatran and the intermediates in pig; and 2) to test a simple in vitro methodology for quantitative investigations of membrane transporters impact on the disposition of metabolized drugs. Methods: Porcine S1 (supernatant fraction obtained by centrifuging at 1000g for 10 min) liver fractions and hepatocytes were incubated in absence and presence of known membrane transporter inhibitors. The in vitro kinetics and disposition were determined by simultaneously fitting of the disappearance of ximelagatran and appearance of ethylmelagatran, N-hydroxymelagatran and melagatran. Results: In S1 liver fractions, the metabolism was significant inhibited by co-incubation of verapamil and ketoconazole but not by erythromycin, quinine and quinidine. The disposition of ximelagatran and the intermediate metabolites in hepatocytes were influenced, to various degrees, by carrier-mediated distribution processes. Conclusion: This work demonstrates that it is possible to obtain profound information of the general mechanisms important in the drug liver disposition with the combination of common in vitro systems and the simple disposition model proposed in this study.

Ort, förlag, år, upplaga, sidor
2010. Vol. 27, nr 4, s. 597-607
Nyckelord [en]
melagatran, prodrug, hepatic disposition, kinetic modeling, hepatocytes
Nationell ämneskategori
Farmakologi och toxikologi
Forskningsämne
Läkemedelsmetabolism
Identifikatorer
URN: urn:nbn:se:uu:diva-110319DOI: 10.1007/s11095-009-0016-yISI: 000275556000007PubMedID: 20140637OAI: oai:DiVA.org:uu-110319DiVA, id: diva2:276139
Tillgänglig från: 2009-11-10 Skapad: 2009-11-10 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Ingår i avhandling
1. Metabolic Studies with Liquid Separation Coupled to Mass Spectrometry
Öppna denna publikation i ny flik eller fönster >>Metabolic Studies with Liquid Separation Coupled to Mass Spectrometry
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Metabolism is the sum of all chemical processes with the purpose to maintain life, as well as enable reproduction, in a living organism. Through the study of metabolism, increased understanding of pharmacological mechanisms and diseases can be achieved. This thesis describes several ways of doing so, including targeted analysis of selected metabolites and investigations of systematic metabolic differences between selected groups through pattern recognition.

A method for exploring metabolic patterns in urine samples after intake of coffee or tea was developed. The methodology was later used with the aim to find biomarkers for prostate cancer and urinary bladder cancer.

Furthermore, a fully automated quantitative method was developed for concentration measurements of the double prodrug ximelagatran and its metabolites in pig liver. The method was then used to study the roll of active transporters in pig liver cells.

Moreover, a fundamental study was conducted to investigate how monitoring of small, doubly charged analytes can improve the limit of detection and precision in a quantitative method.

The techniques used for the experiments were liquid separation coupled to electrospray mass spectrometry. Extra efforts were made to make the separation and the ionization as compatible as possible to each other for increased quality of the collected data.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2009. s. 63
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 690
Nyckelord
liquid chromatography, mass spectrometry, tandem mass spectrometry, method development, capillary electrophoresis, electrospray ionization, time-of-flight, quantitation, metabolomics, metabonomics, pattern recognition, ximelagatran, melagatran, charge state
Nationell ämneskategori
Analytisk kemi
Forskningsämne
analytisk kemi
Identifikatorer
urn:nbn:se:uu:diva-110310 (URN)978-91-554-7663-2 (ISBN)
Disputation
2009-12-14, C4:301, BMC, Husargatan 3, Uppsala, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-11-24 Skapad: 2009-11-10 Senast uppdaterad: 2009-11-24Bibliografiskt granskad
2. Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation
Öppna denna publikation i ny flik eller fönster >>Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell.

Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes involved in the hepatic drug disposition.

An approach to the estimation of enzyme kinetics based on substrate depletion data from cell fractions was thoroughly evaluated through experiments and simulations. The results that it provided were confirmed to be accurate and robust. In addition, a new experimental setup suitable for a screening environment, i.e., for a reduced number of samples, was generated through optimal experimental design. The optimization suggested that sampling at late time points over a wide range of concentration was the most advantageous.

A model, based on data from primary hepatocytes in suspension, for the investigation of cellular disposition of metabolized drugs was developed. Information on the relative importance of metabolism and membrane protein related distribution was obtained by analysis of changes in the kinetics by specific inhibition of the various processes. The model was evaluated by comparing the results to those obtained from an in vivo study analyzed with an especially constructed mechanistic PBPK model. These investigations showed that the suggested model produced good predictions of the relative importance of metabolism and carrier mediated membrane transport for hepatic disposition.

In conclusion, new approaches for the investigation of processes involved in hepatic disposition were developed. These methods were shown to be robust and increased the output of information from already commonly implemented in vitro systems.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2010. s. 72
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 132
Nyckelord
Hepatic disposition, pharmacokinetics, mechanistic modelling, drug-drug interactions, enzyme kinetics, Vmax, Km, CLint, carrier-mediated transport, active transport, modelling, in vitro-in vivo extrapolation, physiologically based pharmacokinetic model, optimal experimental design, experimental optimization, data analysis optimization
Nationell ämneskategori
Farmaceutiska vetenskaper Farmaceutiska vetenskaper
Forskningsämne
Biofarmaci
Identifikatorer
urn:nbn:se:uu:diva-132571 (URN)978-91-554-7934-3 (ISBN)
Disputation
2010-12-10, B:21, Uppsala Biomedicinska Centrum - BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-11-18 Skapad: 2010-10-21 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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