Clinical evidence suggested patients with lower plasma C-reactive protein (CRP) levels after statin therapy could have better clinical outcome. The last part of the study was to measure on-treatment high sensitivity CRP (hsCRP) levels among 229 Chinese patients with hyperlipidaemia undergoing treatment with simvastatin 40 mg daily. The patients were genotyped for 15 SNPs or haplotypes in 11 candidate genes that would have significant allele frequency among Chinese patients and may be linked to statin efficacy or hsCRP levels. The analysis suggested BMI is the largest single contributing factor of 15.0% of the variation in hsCRP levels, followed by plasma triglycerides levels contributing 4.7% and male gender 1.6% (all P<0.05). However comparisons of hsCRP levels among genotype groups did not reveal any significant findings, with or without adjustment with covariate genotypic or phenotypic factors. To further categorize individuals as high or medium risk, we set a threshold hsCRP level of 1 mg/L as the benchmark for evaluation. The CRPc.3872G>A SNP was related to lower risk compared to the homozygous wild-type genotype (adjusted odds ratio AOR = 0.289; P = 0.014) after adjusting for phenotypic factors of age, gender, smoking status, BMI, waist circumference, hip circumference, plasma lipid profiles, co-existing disease and co-medications. Another marginal finding included the HNF1A c.79A>C SNP (AOR = 0.575; P = 0.118). / Polymorphisms in the drug transporters are likely to be more important with hydrophilic statins such as pitavastatin, which undergoes transporter mediated distribution. The SLCO1B1 c.388A>G polymorphism in the gene encoding the uptake transporter organic anion transporting polypeptide (OATP1B1) is common in Chinese and the variant was associated with increases of 63--68% in maximum plasma concentration and 44--47% in systemic exposure of both the lactone and acid compared to wild-type subjects (P<0.05). Co-administration of pitavastatin with grapefruit juice (GFJ) resulted in a small increase of the area under the plasma concentration time curve (AVC) by 15--16% for both the acid and lactone (P<0.05). However, there was no significant effect on the drug-food interaction in relation to relevant SNPs in the enzymes and transporters examined. / The SNPs examined included those in the genes for the enzymes and transporters involved in the metabolic pathway or the distribution of simvastatin. Cytochrome P450 (CYP) enzymes are involved in hepatic and intestinal metabolism of several statins and simvastatin is known to undergo extensive metabolism via the CYP3A4/3A5 pathway. The common candidate SNPs in the CYP3A4/3A5 enzymes found in Chinese populations include CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 , which are associated with altered enzyme expression and activity. However, no statistically significant relationship was found between these SNPs and a potential phenotypic marker of enzyme activity, the urinary ratio of 6beta-hydroxy-cortisol/cortisol (6beta-OHC/C) concentrations. The analysis of lipid lowering responses in relation to individual SNPs or combinations from gene-gene interactions also revealed no statistically significant findings. In the subgroup of patients with familial hypercholesterolaemia, the CYP3A4*1G, CYP3AP1*3 and CYP3A5*3 polymorphisms appeared to have a small effect on the changes in LDL-C and total cholesterol with the subjects with the CYP3A5*3 and CYP3AP1*3 variants showing less reduction and those with the CYP3A4*1G variant showing more reduction than subjects with the wild-type genotype with a tendency for a gene-dose effect. It is difficult to interpret these findings and the significance may be related to multiple testing. / The statins, or 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, act on the rate limiting step in endogenous cholesterol synthesis. Their primary action results in reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels and this is thought to be the major mechanism by which they reduce cardiovascular events. There are considerable differences between subjects in both the plasma levels of the statins and in their effects on LDL-C and other lipid parameters and some of this variation appears to be related to genetic differences in the pathways of drug metabolism and distribution and in the pathways involved in lipid metabolism. / The variation in response may be related to variations in systemic or hepatic exposure to the drug, which in turn will be related to the pharmacokinetics. This is also likely to play a role in the adverse effects of myopathy and therapeutic tolerance. In a pharmacokinetic study in healthy male Chinese subjects, the common polymorphism of CYP2D6*10 was analyzed in relation to the pharmacokinetics of lovastatin and simvastatin. There was a tendency for reduced clearance of simvastatin lactone by 30% (P>0.05) in subjects with the CYP2D6*10/*10 genotype. With lovastatin, there were similar findings with 38.5--84.9% decrease in clearance which appeared to be related to enzyme activity according to genotype, with *5 carriers showing a greater decline in clearance than *10 carriers (P<0.05). / These results provide some insights into the pharmacokinetics and pharmacodynamics of statins and the pharamacogenetic relationships to candidate SNPs. Future research in this field should help to facilitate safer and more effective treatment with these commonly used medications, resulting in personalized therapy and optimal clinical benefits for patients with cardiovascular disease. / This thesis describes a study of 270 patients recruited from the outpatient clinics at the Prince of Wales Hospital who were treated with simvastatin 40 mg daily for at least 4 weeks. Their mean (+/-SD) LDL-C baseline level was 5.38+/-1.68 mmol/L and the reduction in LDL-C after simvastatin treatment was 2.81+/-0.99 mmol/L or -47.1+/-12.5%. / Mak, Wah Lun Valiant. / Adviser: Brian Tomlinson. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 253-289). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344982 |
| Date | January 2011 |
| Contributors | Mak, Wah Lun Valiant., Chinese University of Hong Kong Graduate School. Division of Medical Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxxviii, 289 leaves : ill.) |
| Coverage | China, Hong Kong, Hong Kong |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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