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Projects / Programmes source: ARIS

Pharmacogenetic study of raloxifene metabolism and transport

Research activity

Code Science Field Subfield
1.09.00  Natural sciences and mathematics  Pharmacy   

Code Science Field
B740  Biomedical sciences  Pharmacological sciences, pharmacognosy, pharmacy, toxicology 
Keywords
Raloxifene, UGT, glucuronides, metabolism, transport, pharmacokinetics, polymorphism, (TA)n
Evaluation (rules)
source: COBISS
Researchers (5)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  24399  PhD Igor Locatelli  Pharmacy  Researcher  2008 - 2011  273 
2.  06086  PhD Aleš Mrhar  Pharmacy  Head  2008 - 2011  1,161 
3.  23549  PhD Robert Roškar  Pharmacy  Researcher  2008 - 2011  301 
4.  23420  PhD Jurij Trontelj  Pharmacy  Researcher  2008 - 2011  254 
5.  22659  PhD Simon Žakelj  Pharmacy  Researcher  2008 - 2011  162 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,536 
Abstract
Raloxifene (Ral) is a new member of drugs used for the prevention of osteoporosis in postmenopausal women. The source of the large (CV 30-50%) variability in its pharmacokinetic parameters is not yet known. Ral is subjected to an extensive phase-II metabolism in the intestinal mucosa and in the liver. Our hypothesis is that the main metabolic enzyme responsible for the conjugation and subsequent elimination of raloxifene is UGT1A1. The promoter region in the UGT1A1 gene carries a frequent polymorphism (TA)7, which causes a lesser UGT1A1 transcription. Homozygous state (TA)7/(TA)7 leads to a Gilbert syndrome, which is a quite common billirubin conjugation defect that can reach a frequency of up to 36 %. The (TA)7 polymorphism may also be one of the main causes for the variability in raloxifene pharmacokinetics. The objectives of the proposed project are: 1) to study Ral transport and metabolism in the small intestine, liver and kidney, 2) to determine if there is a connection between the (TA)7 polymorphism and Ral serum concentrations and 3) if the polymorphism effect is consequently reflected on Ral pharmacodynamics. In order to achieve these research goals, several in vitro models will be used: Supersomes™ with UGTs, porcine and human liver, intestinal and kidney microsomes and the Sweetana Grass type diffusion chambers. Serum samples obtained from a group of 47 osteoporotic female patients on raloxifene therapy will be analyzed by LC-MS-MS and genotyped for the presence of (TA)7 polymorphism. The therapeutic effect of raloxifene will be assessed by determination of the change in bone mineral density after one year of raloxifene therapy. The synergistic experimental approaches, employing different in vitro models with increasing complexity will enable us to understand the kinetics and mechanisms involved in raloxifene transport and metabolism in multiple organs in human body. The acquired knowledge from the proposed research project will provide a significantly better understanding of raloxifene pharmacokinetics in humans in vivo.
Significance for science
The results of the performed research clarify to a large extent the complex raloxifene transport and metabolic processes and provide explanation of the high variability in its pharmacokinetic parameters. We expect our findings to bring a significant contribution to better understanding of absorption, metabolism, distribution and elimination of raloxifene. New experimental approaches were introduced by applying an integrated use of several in vitro models for studying transport and metabolism at the same time in the viable intestinal mucosa and in the liver. These models gave a better insight into the absorption, presystemic and systemic metabolism of raloxifene. Moreover, the same approach can be used later, in studying and predicting the absorption and metabolism of other drugs with first-pass effect. The performed research is also an important step forward because we included in our investigations the study of influences of genetic factors on drug response. These factors significantly alter the response of an individual to drug therapy. By doing so, we significantly contributed to the development of an emerging and ever more interesting science – pharmacogenomics, the ultimate goal of which is to apply the knowledge of individual's genetic characteristics to adjust her/his drug therapy and thus to achieve a safer and more effective treatment.
Significance for the country
The research within this project and the obtained results are especially focused on the discovery of new and socially relevant knowledge in the area of "health and life sciences". This is one of the four key research areas as defined by the Resolution of national research and development program for the 2006-2010 period (ReNRRP), Uradni list RS, št. 3/2006. The results of the project will significantly contribute to the development of an emerging science of pharmacogenomics, which studies the relationship between the individuals genetic characteristics and their responses to drug therapy. The interest in the investigated drug raloxifene is increasing because its primary indication (treatment of osteoporosis) has been broadened by a newly discovered preventive action on invasive breast cancer. Both indications are even more relevant when rapid increase of the elderly population is considered. The entirely new knowledge about the raloxifene drug therapy and the newly developed experimental approaches for the investigation of drug transport and metabolism that this project provides allow us to claim that Slovenian expertise can equally compete at the highest scientific level within this particular research area. This contributes to the international image of Slovenia as a country with top-level research scientists and highly appreciated scientific achievements.
Most important scientific results Annual report 2008, 2009, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2008, 2009, final report, complete report on dLib.si
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