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List of abbreviations 7
I. 서론 14
II. 실험 재료 및 방법 20
1. 시약 및 재료 20
2. 실험 기기 21
3. Genotyping 23
3.1. 피험자 23
3.2. DNA 추출 23
3.3. PCR-RFLP analysis for CYP2C9 polymorphism 24
3.4. CYP2C9 exon의 sequencing 25
4. Study design 26
4.1. Losartan 27
4.2. Irbesartan 28
4.3. Candesartan 28
5. 혈중 약물농도의 분석 29
5.1. Losartan 29
5.1.1. 검량선 작성 29
5.1.2. 혈장시료의 처리 및 혈중농도계산 30
5.1.3. 분석조건 31
5.2. Irbesartan 31
5.2.1. 검량선 작성 31
5.2.2. 혈장시료의 처리 및 혈중농도계산 32
5.2.3. 분석조건 32
5.3. Candesartan 33
5.3.1. 검량선 작성 33
5.3.2. 혈장시료의 처리 및 혈중농도계산 34
5.3.3. 분석조건 34
6. 약동학적 파라메타계산 34
7. 통계 처리 35
III. 결과 36
1. CYP2C9 polymorphism의 확인 36
2. 498명의 한국인에서 CYP2C9의 genotype과 allele의 빈도 37
3. 각 약물의 HPLC 분석 37
3.1. Losartan과 E-3174 37
3.1.1. 특이성 37
3.1.2. 직선성 38
3.1.3. 정밀성, 정확성, 감도(정량한계) 및 회수율 38
3.2. Irbesartan 39
3.2.1. 특이성 39
3.2.2. 직선성 40
3.2.3. 정밀성, 정확성, 감도(정량한계) 및 회수율 40
3.3. Candesartan과 MII 41
3.3.1. 특이성 41
3.3.2. 직선성 41
3.3.3. 정밀성, 정확성, 감도(정량한계) 및 회수율 41
4. CYP2C9의 유전적다형성에 의한 각 약물의 약물동태학적특성 변화 42
4.1. Losartan과 E-3174 42
4.2. Irbesartan 43
4.3. Candesartan과 MII 44
5. CYP2C9의 유전적다형성에 의한 각 약물의 약력학적변화 45
IV. 고찰 83
V. 결론 90
VI. 참고 문헌 92
Abstract 102
Table 1. Individual demographic characteristics and genotypic background of CYP2C9 of 26 subjects (for losartan study) 46
Table 2. Individual demographic characteristics and genotypic background of CYP2C9 of 20 subjects (for irbesartan study) 47
Table 3. Individual demographic characteristics and genotypic background of CYP2C9 of 22 subjects (for candesartan study) 48
Table 4. Allele and genotype frequencies of CYP2C9 in 498 Korean subjects 53
Table 5. Allele frequencies for CYP2C9 in different Asian populations 54
Table 6. Precision, accuracy and recovery of HPLC assay method for plasma losartan (A) and E-3174 (B) (n=5 for precision and accuracy, n=3 for recovery) 57
Table 7. Precision, accuracy and recovery of HPLC assay method for plasma irbesartan (n=5 for precision and accuracy, n=3 for recovery) 60
Table 8. Precision, accuracy and recovery of HPLC assay method for plasma candesartan (n=5 for precision and accuracy, n=3 for recovery) 63
Table 9. Pharmacokinetic parameters of losartan and E-3174 in the CYP2C9*1/*1 (n=13, circles), CYP2C9*1/*3 (n=11, squares) and CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 50 mg oral dose of losartan 66
Table 10. Pharmacokinetic parameters of irbesartan in the CYP2C9*1/*1 (n=10, circles), CYP2C9*1/*3 (n=9, squares) and CYP2C9*1/*13 (n=l, triangle) genotype groups after a single 150 mg oral dose of irbesartan 72
Table 11. Pharmacokinetic parameters of candesartan and MII in the CYP2C9*1/*1 (n=14, circles), CYP2C9*1/*3 (n=6, squares) and CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 16 mg oral... 77
Figure 1. Oxidative biotransformation of losartan to its active carboxylic acid metabolite. The conversion of losartan to E-3174 is catalyzed by the CYP family and that both CYP2C9 and CYP3A4 is... 19
Figure 2. Chemical structure of irbesartan. 19
Figure 3. Chemical structure of candesartan cilexetil (A), candesartan (B) and MII. 19
Figure 4. PCR-RFLP analysis for CYP2C9*3. Genomic DNA amplified with two separate mismatched primers and an reverse primer.... 49
Figure 5. DNA sequencing of CYP2C9 exon 7. Spectrum of a wild-type (left) and the heterozygous type for CYP2C9*3 allele (right). SNP points are indicated by an arrow. 50
Figure 6. PCR-RFLP analysis for CYP2C9*13. PCR product (689 bp) amplified from genomic DNA with the restriction enzyme PspG1 and electrophoresed on 3% agarose gel.... 51
Figure 7. DNA sequencing of CYP2C9 exon 2-3. Spectrum of a wild-type (left) and the heterozygous type for CYP2C9*13 allele (right). SNP points are indicated by an arrow. 52
Figure 8. HPLC chromatograms of losartan, E-3174 and internal standard (IS, valsartan) in human plasma. 55
Figure 9. Calibration curve of plasma losartan (A, n=9) and E-3174 (B, n=9). 56
Figure 10. HPLC chromatograms of irbesartan and internal standard (IS, valsartan) in human plasma. 58
Figure 11. Calibration curve of plasma irbesartan (n=9). 59
Figure 12. HPLC chromatograms of candesartan, MII and internal standard (IS, valsartan) in human plasma. 61
Figure 13. Calibration curve of plasma candesartan (n=9). 62
Figure 14. Plasma concentration-time profiles of losartan in the CYP2C9*1/*1 (n=13, circles), CYP2C9*1/*3 (n=11, squares), CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 50 mg... 64
Figure 15. Plasma concentration-time profiles of E-3174 in the CYP2C9*1/*1 (n=13, circles), CYP2C9*1/*3 (n=11, squares), CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 50 mg... 65
Figure 16. Values for maximum plasma concentration of losartan (A) and elimination half-life of losartan (B) in relation to the CYP2C9 genotype. The median value in each genotype group is indicated by the horizontal... 67
Figure 17. Values for apparent oral clearance of losartan (A) and area under plasma-time curve from time 0 to infinity (AUC0-∞) of losartan (B) in relation to the CYP2C9 genotype....(이미지참조) 68
Figure 18. Values for elimination half-life of E-3174 (A) and maximum plasma concentration of E-3174 (B) in relation to the CYP2C9 genotype.... 69
Figure 19. Values for ratio of the losartan plasma maximum concentration to the E-3174 plasma maximum concentration (A) and ratio of the losartan plasma AUC0-∞ to the E-3174 plasma AUC0-∞...(이미지참조) 70
Figure 20. Plasma concentration-time profiles of irbesartan in the CYP2C9*1/*1 (n=10, circles), CYP2C9*1/*3 (n=9, squares), CYP2C9*1/*13 (n=1, triangle) genotype groups after a single 150 mg... 71
Figure 21. Values for maximum plasma concentration of irbesartan (A) and elimination half-life of irbesartan (B) in relation to the CYP2C9 genotype. The median value in each genotype group is indicated by the horizontal... 73
Figure 22. Values for apparent oral clearance of irbesartan (A) and area under plasma-time curve from time 0 to infinity (AUC0-∞) of irbesartan (B) in relation to the CYP2C9 genotype....(이미지참조) 74
Figure 23. Plasma concentration-time profiles of candesartan in the CYP2C9*1/*1 (n=14, circles), CYP2C9*1/*3 (n=6, squares), CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 16 mg... 75
Figure 24. Plasma concentration-time profiles of MII in the CYP2C9*1/*1 (n=14, circles), CYP2C9*1/*3 (n=6, squares), CYP2C9*1/*13 (n=2, triangles) genotype groups after a single 16 mg... 76
Figure 25. Values for maximum plasma concentration of candesartan metabolite (MII) (A) and apparent oral clearance of MII (B) in relation to the CYP2C9 genotype.... 78
Figure 26. Values for area under plasma-time curve from time 0 to infinity (AUC0-∞) of MII in relation to the CYP2C9 genotype. The median value in each genotype group is indicated by the horizontal line....(이미지참조) 79
Figure 27. Values for ratio of the candesartan plasma maximum concentration to the MII plasma maximum concentration of the candesartan (A) and ratio of candesartan plasma AUC0-∞ to the MII...(이미지참조) 80
Figure 28. Mean changes in systolic (A) and diastolic (B) blood pressure-time profiles (mean±SEM) after oral administration of a single dose of irbesartan in CYP2C9*1/*1 (n=10, circles),... 81
Figure 29. Mean changes in systolic (A) and diastolic (B) blood pressure-time profiles (mean±SEM) after oral administration of a single dose of candesartan in CYP2C9*1/*1 (n=14, circles),... 82
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