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Studie zu erblichen Einflüssen auf die Pharmakokinetik von Midazolam und Koffein

Study for the evaluation of heritability of midazolam and caffeine pharmacokinetics

Jakob Strube
Doctoral thesis
Date of Examination: 2015-04-29
Date of issue: 2015-04-23
Advisor: Brockmöller, Jürgen Prof. Dr.
Referee: Brockmöller, Jürgen Prof. Dr.
Referee: Bickeböller, Heike Prof. Dr.
Referee: Konietschke, Frank PD Dr.

Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-5FBE-E

 

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Abstract

English

The individual effects of drug reaction is subject to large interindividual variations. Based on a better understanding of the causes of these variations and a customization of pharmacotherapies an improvement of the effects and minimization of the side effects is to be expected. A large part of the interindividual variability in pharmacokinetics is based on the different activity of CYP enzymes. Important representatives of these metabolic enzymes are CYP1A2 and CYP3A4, which are involved in the metabolism of a large number of drugs. In this work - as part of a comprehensive pharmacokinetic twin study – the hereditary part of thevariability of the activity of CYP3A4, CYP3A5 and CYP1A2 was examined with the test substances midazolam and caffeine. Based on the correlations and the variability of pharmacokinetic parameters of the test substances and their primary metabolites hydroxymidazolam and paraxanthine the hereditary component was estimated by three twin dependent and one twin independent method. It was estimated from the correlation coefficients by comparing the mono- and dizygotic twin groups with the formulas introduced by Falconer and Vesell and furthermore calculated with a structural equation model. It was also estimated based on the inter- and intra-individual variability according to the twin independent method published by Kalow. With these four different methods distinctly different results were found. The in vivo activity of CYP3A4 and CYP3A5 was calculated based on the clearance and AUC of midazolam and hydroxymidazolam. In the calculation according to Falconer a heritability of a maximum of 75% and according to Vesell of 52% was estimated. The structural equation model analysis based on the AUC showed a heritability of 20%. The twin independent method by Kalow resulted in a heritability of 77%. The in vivo activity of CYP1A2 was calculated based on the clearance and AUC of caffeine and paraxanthine. For the enzyme activity of CYP1A2 a heritability of 22% was estimated according to the formula of Falconer and of 37% according to the formula of Vesell. The structural equation model analysis based on the AUC showed no genetic component. The method by Kalow estimated a heritability of 93%. A similar comparison of these four different estimation methods for heritability was not found in the literature. In this study in almost all calculations the highest hereditary component was estimated according to the method of Kalow and the lowest according to the structural equation model analysis. It can be assumed that the formulas of Falconer, Vesell and Kalow are only estimations for the heritability. A further comparison of the four methods used in this work to determine heritability and examine the reasons for the different results in a larger twin study would be of interest. In view of individualized medicine further steps are also required. On one hand to investigate a possible correlation of different genotypes and enzyme activity and on the other hand to investigate a more detailed understanding of the environmental factors and their considerable effects to enzyme activity.
Keywords: heritability; midazolam; caffeine; pharmacokinetics; CYP1A2; CYP3A4
Schlagwörter: Erblichkeit; Midazolam; Koffein; Pharmakokinetik; CYP1A2; CYP3A4
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