Despite the fact that RYR products contain lovastatin and, in some countries, can be classified as drugs, in Asia, they are still considered as a food or dietary supplement and are widely available to the public. A number of studies have demonstrated the cholesterol lowering efficacy of RYR products [2
], which were generally demonstrated to be well tolerated, with few safety concerns [10
]. However, consumption of RYR products has been associated with occurrence of myopathy, rhabdomyolysis, or hepatitis in several case reports [18
]. Although RYR contains many components, it is generally believed that lovastatin is mainly responsible for the efficacy of RYR products. However, there is little information on the pharmacokinetic properties of lovastatin in these products. In this study, we first showed that extracts of different RYR products at the same lovastatin concentration differed in their ability to inhibit CYP450 enzymes and P-gp and LipoCol Forte, Xuezhikang, and Cholestin extracts at the same lovastatin content were more effective in inhibiting CYP3A4 and/or P-gp than pure lovastatin. It is also noted that extracts of LipoCol Forte and Xuezhikang had comparable inhibitory potencies to typical inhibitors of CYP2C19 and CYP1A2, suggesting their potential interaction with drugs that are primarily metabolized by these enzymes.
Lovastatin is metabolized by CYP3A4 [14
] and is a substrate of P-glycoprotein (P-gp) [15
]. The concomitant use of potent inhibitors of CYP3A4 or P-gp with lovastatin can significantly increase systemic exposure of lovastatin and lovastatin acid [30
]. Despite the observation that RYR product extracts could inhibit CYP450 enzymes (including CYP3A4) and P-gp in vitro, the pharmacokinetic properties in healthy volunteers of lovastatin and its active metabolite, lovastatin acid, were found to be linear in the dose range of 1 to 4 LipoCol Forte capsules taken as a single dose and no significant accumulation was observed after multiple dosing. Thus, its pharmacokinetic properties in healthy volunteers are predictable within the recommended dose range.
It is suggested that the potential drug interactions can be evaluated in vitro by calculating the values of I1
, in which I1
are the maximal plasma concentration at steady-state at the highest clinical dose and the oral molar concentration (oral dose divided by 250
mL) at the luminal side of gastrointestinal, respectively [32
]. The average dosing of RYR products ranges from 600 to 1800
mg given twice daily [9
]. Despite the variation, the amount of lovastatin for each RYR dosing is about 5
mg, similar to one capsule (600
mg) of LipoCol Forte. In this regard, taking LipoCol Forte as an example, I1
values for RYR product to inhibit CYP3A4 and P-gp are about 0.001 and 0.0001 for CYP3A4 and p-gp, respectively. Both are below the suggested cut-off value of 0.1 [32
], suggesting no potential interaction. On the other hand, I2
values for RYR product to inhibit CYP3A4 and P-gp are 18 and 2.1, respectively. According to FDA guidance, this suggests the likelihood of in vivo interaction between RYR and CYP3A4 substrates, based on the I2
value of larger than 10 [33
]. Previous study suggests no significant interaction between lovastatin and nifedipine, a substrate of CYP3A4 [35
]. However, our data suggest that RYR is more potent than lovastatin in inhibiting CYP3A4 and may interact with nifedipine in vivo. Accordingly, the effects of RYR (one 600
mg LipoCol Forte capsule) on the pharmacokinetic properties of nifedipine were investigated in healthy volunteers. The results showed that the concomitant use of LipoCol Forte had no effects on the pharmacokinetic properties of nifedipine, probably due to the marginal I2
ratio at this dose. Alternatively, solubility problem may lead to false-positive estimation utilizing the proposed I2
]. Nonetheless, the effects of RYR at higher doses need to be further confirmed.
Given that occurrence of RYR-associated adverse reactions has usually been reported in patients with concomitant comedications [18
], possible drug-RYR product interactions need to be further addressed. Due to limited information, most potential drug-RYR product interactions are inferred from known drug-drug interactions for statins. Among these, an interaction between fibrates and statins has been noted by the US FDA [38
]. Fibrates are carboxylic acids that are commonly used in conjunction with statins to treat hyperlipidemia and it has been observed that concomitant use of the fibrate gemfibrozil with Mevacor markedly increases plasma concentrations of the active lovastatin acid without affecting those of the parent lovastatin [29
]. Likewise, in the present study, the concomitant use of gemfibrozil and LipoCol Forte increased plasma concentrations of lovastatin acid without affecting lovastatin levels. It has been demonstrated that lovastatin acid is metabolized by CYP2C8 [39
], whereas gemfibrozil and its glucuronide metabolite are inhibitors of CYP2C8 [39
]. Gemfibrozil may also inhibit the OATP1B1-mediated hepatic uptake of lovastatin acid, as it was reported for other statin acids [40
]. These may be the reasons why gemfibrozil increased the AUC value of the active lovastatin acid but not of the parent lovastatin.
A number of drugs, including fibrates, azole anti-fungals, macrolide antibiotics, anti-arrhythmics, and protease inhibitors, may increase the plasma levels of statins, through the inhibition of CYP3A4, P-gp, or OATP1B1 [30
]. Given that RYR is a lovastatin-containing drug, the concomitant use of these drugs with RYR should be cautious, as it was demonstrated in the gemfibrozil case in the present study. On the other hand, since RYR had comparable inhibitory potencies to typical inhibitors of CYP1A2 and CYP2C19, the interaction between RYR and substrates of CYP1A2 (e.g., verapamil) [41
] and/or CYP2C19 (e.g., clopidogrel, a drug that is activated by both CYP1A2 and CYP2C19) [42
] is worth an attention. In particular, for CYP2C19, 13% to 23% of Asian populations are CYP2C19 poor metabolizers and the pharmacokinetics and pharmacodynamics of CYP2C19 substrates are dependent on CYP2C19 genotypes [44
]. In this regard, it is noteworthy to study the effects of RYR on the metabolism of CYP2C19 substrates in CYP2C19 poor metabolizers.