slutligen lämna kroppen genom utsöndring. Nedbrytning av kroppsfrämmande ämnen såsom läkemedel kallas för metabolism. Läkemedelsmetabolism betraktas ofta som en process som förändrar läkemedel till ofarliga, vattenlösliga nedbrytningsprodukter som lätt kan lämna kroppen, t.ex. via urinen. Läkemedel kan emellertid även omvandlas till reaktiva och potentiellt toxiska nedbrytningsprodukter (metaboliter) genom meta-bolism. Sådana reaktiva metaboliter kan binda till olika proteiner eller till DNA i kroppen, vilket kan ge biverkningar och skador hos patienter. Reaktiva metaboliter försvårar på detta sätt användandet och utvecklingen av nya läkemedel. Det är därför viktigt att utveckla metoder för att tidigt i utvecklingen av läkemedel identifiera samt undvika reaktiva metaboliter.
Denna avhandling utreder hur elektrokemiska metoder kan användas för att studera reaktiva metaboliter. I delarbete I vidareutvecklades och förfinades metoder för att efterlikna metabolismen av läkemedel i kroppen med hjälp av tre olika kemiska system. Systemen kompletterade varandra och alla relevanta typer av metaboliska reaktioner efterliknades med minst ett av de tre systemen. I delarbete II och III studerades metabolismen av två välkända läkemedel, amodiakin och haloperidol. Amodiakin var ett malarialäkemedel som blev indraget från marknaden på grund av dess allvarliga biverkningar. I detta arbete identifierades hittills okända metaboliter som skulle kunna orsaka eller bidra till amodiakins biverkningar. Elektrokemisk framställning av en av metaboliterna i tillräckliga mängder, möjliggjorde att metabolitens struktur kunde bestämmas. Haloperidol är ett läkemedel som används i behandling av schizofreni och svåra psykoser. Idag är användandet av detta läkemedel begränsat på grund av dess oönskade biverkningar, som tros bero på en av haloperidols metaboliter. I delarbete
III studerades bildningen av denna metabolit och nya, kortlivade produkter
observerades som visade på mellansteg i denna bildning.
Om man i utvecklingen av ett läkemedel upptäcker att en eller flera reaktiva eller toxiska metaboliter bildas vid nedbrytningen i kroppen, finns det olika sätt att hantera problemet. Ett exempel är att på olika sätt ändra på läkemedlets struktur. I delarbete
IV ändrades haloperidols struktur för att undvika att den toxiska metaboliten bildas
Acknowledgements
I would like to express my sincere gratitude to the following people, you have all in different ways contributed to the preparation of this thesis:
My supervisors Dr Lars Weidolf and Dr Ulrik Jurva for giving me the great opportunity to perform my master thesis work in your group and later for taking me on as a Ph.D. student.
Dr Lars Weidolf for always being able to see the overall picture and for contributing with your large knowledge. Thank you for sharing interesting project problems, thorough proofreading of manuscripts and for taking on the responsibility as main supervisor. You have been acting as my mentor as well as my supervisor.
Dr Ulrik Jurva for your endless enthusiasm and encouragement! Thank you for sharing your knowledge of electrochemistry and mass spectrometry, and for always taking time to discuss results or experimental problems. You are one of the most helpful, positive and kindest persons I know!
Dr Kristina Luthman for support and encouragement, always with a warm and positive attitude.
To the Biotransformation group, the old and the new one, for showing interest in my work and for helping me with equipment and questions. Especially thanks to Bo Lindmark, Carina Leandersson and Anna Abrahamsson for answering many questions about the QTOF instruments. Thanks also to Emre Isin for clarifying reactivity issues. Dr Jennie Georgsson for your patient guidance during the synthetic work. Although it did not lead to any publication, I am now able to claim that I have synthesized 200 compounds. Thanks also to the group at KK2 during that time.
Dr Gunnar Grönberg for always being very helpful and open to new, exciting ideas. We did get some really nice NMR spectra!
Dr Collen Masimirembwa for a nice collaboration on the amodiaquine paper. Nothing is impossible when you work with Collen!
Professor Reinhold Tacke for the fruitful collaboration on the sila-compounds. Professor Neal Castagnoli, Jr. for contributing with your knowledge of haloperidol and MS/MS fragmentation, and for generously providing synthetic reference compounds. Dr Martin Kjerrulf for help with setting up a method for isolation of human leukocytes.
Ingvar Nilsson for helping me with the lyophilization with a happy smile!
Dr Anders Tunek, Dr Richard Thompson and Dr Hugues Dolgos for supporting this project.
To all the people that I have worked with during these years, thank you for your support and guidance but also for making the time at AstraZeneca interesting and joyful.
My family and friends:
Jag skulle vilja tacka alla mina släktingar och vänner för ert stöd och för att ni får mig att tänka på andra saker än arbetet.
Uppsalaflickorna, våra årliga träffar har gett mig välbehövlig energi och det är alltid lika trevligt att umgås med er.
Tack till min familj, för stöd i tuffa perioder och för firande av glada stunder. Pappa och Elisabet för att ni alltid lyssnar, stöttar och tror på mig. Min mamma Grethe, du finns alltid i mina tankar och jag önskar att du fick uppleva det här.
Mormor, du betyder så mycket för mig.
Mailis och Niilo, för er omtanke, stöd och intresse i mitt arbete.
Samuel, utan dig hade detta inte varit möjligt. Tack för att du alltid tror på mig, stöttar när det är svårt och gläds när det går bra. Du uppmuntrade mig att söka doktorandtjänsten och du har peppat mig hela vägen. You and me, me and you.
The Swedish Academy of Pharmaceutical Sciences, Stiftelsen Kjellbergska Flickskolans Donationer, Adlerbertska Foundation Travel Grant for travel and conference support.
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