The effects of co-administering the flavonoids quercetin and biochanin A on simvastatin toxicity in HepG2 cultures

Aims

Inhibition of hepatic organic anion transporter polypeptide 1B1 (OATP1B1) or cytochrome 3A4 (CYP3A4) via pharmacokinetic interactions is known to increase the risk of simvastatin-induced myopathy. The flavonoids quercetin and biochanin A are known to inhibit both OATP1B1 and CYP3A4, however it is unknown whether co-administration of these flavonoids with simvastatin is likely to lead to myopathy. Thus, quercetin and biochanin A were co-administered with simvastatin to investigate whether hepatic absorption or metabolism was inhibited.

Main methods

The hepatic carcinoma cell line, HepG2 cells was used to model pharmacokinetic interactions. CYP3A4 activity in the HepG2 cultures was confirmed through rifampicin (40 µM) pre-treatment inducing paracetamol (20–50 mM) toxicity. OATP activity in HepG2 cultures was validated using the fluorescent probe pyranine (0–50 µM), followed by inhibition of specific pyranine uptake by the flavonoids quercetin and biochanin A and the drugs gemfibrozil and diltiazem. Toxicity screenings were performed using an MTT assay for simvastatin (20–50 µM) in the absence or presence of diltiazem, gemfibrozil, quercetin and biochanin A (40 µM).

Key findings

Quercetin and biochanin A (40 µM) inhibited specific pyranine uptake comparable to the known OATP inhibitor gemfibrozil (40 µM) (n = 4, P ≤ 0.05). 40 µM of gemfibrozil significantly reduced simvastatin toxicity at 20 µM (n = 4, P ≤ 0.05). Quercetin and diltiazem (40 µM) did not modulate simvastatin toxicity. Biochanin A at 40 µM significantly induced simvastatin toxicity at concentrations 20–50 µM (n = 4, P ≤ 0.05).

Significance

Quercetin and biochanin A inhibited OATP, possibly implicating them in drug-drug interactions, but simvastatin toxicity in HepG2 cells was not attenuated as initially hypothesised. Biochanin A significantly synergistically increased simvastatin toxicity in HepG2 cultures, which warrants further studies.