The significance of OATP and CYP450 in statin-flavonoid interactions
| dc.contributor.advisor | Musgrave, Ian | |
| dc.contributor.advisor | Byard, Roger | |
| dc.contributor.advisor | Farrington, Rachael | |
| dc.contributor.author | Zechner, Joshua | |
| dc.contributor.school | School of Biomedicine | en |
| dc.date.issued | 2023 | |
| dc.description.abstract | Statins are the most prescribed drug world-wide as a first-line defence to hypercholesteraemia. In rare cases, statins can have adverse events such as myotoxicity which can further progress to a potentially fatal condition, rhabdomyolysis. This risk is exacerbated by drug-drug interactions between statins and conventional medicines that may inhibit metabolic pathways important to statin clearance. Though drug-drug interactions are well characterised with statins, there has been little investigation into herb-drug interactions with statins. Herbal medicines are a type of complementary and alternative medicine (CAM). Concerningly it is known that CAMs are commonly used by those suffering from a chronic condition such as cardiovascular disease in addition to their conventional treatment. There is evidence that a class of phytochemicals known as flavonoids may be able to inhibit hepatic absorbance and metabolism, comparable to drugs that are known to have drug-drug interactions with statins. Chapter 1: “Flavonoid-statin interactions causing myopathy and the possible significance of OATP transport, CYP450 metabolism and mevalonate synthesis” reviews what is currently know about how flavonoids may interact with statin hepatic transport and metabolism, identifies what flavonoids are inhibitors of these pathways, how this compares to known conventional inhibitors and attempts to highlight some proposed mechanisms of toxicity. Flavonoids such as quercetin and biochanin A were identified to be inhibitors of CYP3A4 and OATP1B1 which are pathways important to statin uptake and metabolism. Additionally, there are implications for these flavonoids to have pharmacodynamic interactions with statins through the cholesterol synthesis pathway. The risk for statin-induced myotoxicity starts with the inhibition of statin uptake and/or metabolism within the liver. Chapter 2: “The effects of co-administering the flavonoids quercetin and biochanin A on simvastatin toxicity in HepG2 cultures” built off the discussion in chapter 1 and tested the co-administration of the flavonoid’s quercetin and biochanin A with simvastatin in a hepatic carcinoma cell line (HepG2). This study investigated if these flavonoids could modulate simvastatin’s toxicity through CYP3A4 inhibition or through OATP inhibition. Comparison was also conducted between simvastatin-induced hepatotoxicity with flavonoid modulation and known conventional cytochrome P450 3A4 (CYP3A4) and organic anion transporter polypeptide (OATP) inhibitors, diltiazem, and gemfibrozil, respectively. OATP activity was validated using a fluorescent probe known as pyranine and tested if quercetin or biochanin A would inhibit pyranine uptake, which is the first time this assay has been used for uptake inhibition in a non-transfected cell line. Finally, the findings of the two chapters are summarised and future directions are suggested in the discussion of this thesis. | en |
| dc.description.dissertation | Thesis (M.Phil.) -- University of Adelaide, School of Biomedicine, 2023 | en |
| dc.identifier.uri | https://hdl.handle.net/2440/139043 | |
| dc.language.iso | en | en |
| dc.provenance | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals | en |
| dc.subject | Statins, hepatoxicity, myopathy, flavonoids, herbal | en |
| dc.title | The significance of OATP and CYP450 in statin-flavonoid interactions | en |
| dc.type | Thesis | en |
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