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5929_06_p1031-1038

THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE
Volume 11, Number 6, 2005, pp. 1031–1038
Mary Ann Liebert, Inc.

Plasma Clearance of Lovastatin Versus Chinese ZHAOPING LI, Ph.D., M.D., NAVINDRA P. SEERAM, Ph.D., RUPO LEE, M.Sc., GAIL THAMES, B.A., CHAYO MINUTTI, HE-JING WANG, M.P.H., M.D., and DAVID HEBER, Ph.D., M.D.
ABSTRACT
Objectives: It is now accepted that inhibition of cholesterol biosynthesis is effective in the primary and sec-
ondary prevention of heart disease. However, the perceived side-effects on muscle and liver reduce the generalacceptance of statin drug therapy as well as compliance over the long term, which is necessary for preventionefforts to be successful. Chinese red yeast rice (CRYR) is a supplement containing lovastatin (monacolin K),eight other monacolins, pigments, tannins, and other phytochemicals. The authors previously reported on a dou-ble-blind placebo-controlled trial of CRYR supplement in 80 individuals demonstrating a significant decreasein cholesterol levels from 250 mg/dL to 210 mg/dL over 8 weeks independent of diet. The current study com-pared the pharmacokinetics of CRYR with lovastatin at the same bioeffective dose for lowering cholesterol.
Methods: Eleven (11) healthy volunteers were randomized to a crossover study taking 2400 mg CRYR or
Results: The Cmax and area under the curve (AUC) of lovastatin were 22.42 ng/mL, and 80.47 higher than
CRYR (p ϭ 0.001 and 0.002, respectively). The Cmax for lovastatin hydroxy-acid was 36.63 ng/mL higher thanthe Cmax of CRYR hydroxy-acid (p ϭ 0.001). The AUC of lovastatin hydroxy-acid was 258.5 greater than thatof CRYR (p ϭ 0.001).
Conclusions: The results suggested that the effect of CRYR on the cholesterol concentration might be caused
by the additive and/or synergistic effects of monacolin K with other monacolins and substances in CRYR. Itmay lead to the ultimate development of a botanical supplement based on CRYR.
INTRODUCTION
prevention rather than taking drugs,2,3 and view these as nat-ural alternatives to drug therapy.
It is now accepted that inhibition of cholesterol biosyn- Chinese red yeast fermented on rice is a traditional food
thesis is effective in the primary and secondary preven- consumed throughout Asia. Its food value and medicinal value tion of heart disease. Statin drugs, which are competitive in- date back prior to its first recorded use in 800 AD.4,5 A die- hibitors of HMG-CoA reductase, lower cholesterol levels tary supplement of Chinese red yeast rice (CRYR) has been and reduce the progression of atherosclerotic lesions while prepared that contains only a selected strain of Monascus pur- also stabilizing pre-existing atheromatous plaques. The per- pureus Went yeast and white rice on which it was fermented.
ceived side-effects on muscle and liver reduce the general There are a number of constituents in the supplement includ- acceptance of statin drug therapy as well as compliance over ing pigments, fatty acids, and polyketides (monacolins).6 the long term, which are necessary for prevention efforts to The authors previously reported on a double-blinded be successful.1 Surveys demonstrate that many Americans placebo-controlled trial of this CRYR supplement in 80 in- often turn to alternative herbal therapies for heart disease dividuals demonstrating a significant decrease in cholesterol Center for Human Nutrition, David Geffen School of Medicine, University of California, Los Angeles, CA.
TABLE 1. CONSTITUENTS OF CHINESE RED YEAST RICE by inhibiting CYP3A4-mediated first-pass metabolism in the small intestine. The present study uses the preceding method to increase the detectable levels of monacolins.
The subjects were given 200 mL of double-strength grapefruit juice (Minute Maid frozen concentrated grape- fruit juice, 12 fluid ounces (355 mL), Coca-Cola Foods, Houston, TX) three times per day (at 7 AM, noon, and 8 PM) for 2 days. On day 3, the subjects reported to the GCRC at 7:30 AM after fasting from 11 PM the previous day. A caf- feine-free standardized breakfast was served at 7:45 AM and either 20 mg of lovastatin or 2400 mg of Chinese red yeast rice was given with 200 mL of double-strength grapefruit juice at 8 AM. Standardized lunch and dinner were served at noon and 5 pm. The subjects returned to the GCRC the next morning to have their blood last drawn at 8 AM.
On the day of administration of lovastatin or CRYR, a forearm vein of each subject was cannulated with a plasticcannula and kept patent with a heparin flush. Blood sam- levels from 250 mg/dL to 210 mg/dL over 8 weeks inde- ples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 pendent of diet.7 The current study was designed to com- hours after taking lovastatin or taking CRYR. Whole blood pare the pharmacokinetics of CRYR with lovastatin at the was centrifuged immediately and plasma transferred to plas- same bioeffective dose for lowering cholesterol to determine tic tubes and frozen at Ϫ80°C until assay.
whether the body metabolizes complex mixtures of naturalsubstances found in CRYR differently than lovastatin.
Methodology for determination of monacolin K (lovastatin) and lovastatin hydroxy-acid in human plasma Lovastatin 20–mg capsules were purchased from Merck & Co. Inc. (Whitehouse, NJ) CRYR dietary supplement 600- mg capsules were provided by Beijing WBL Peking Uni- The study protocol was approved by the Ethics Commit- tee of the University of California, Los Angeles and con- HPLC-MS analyses were carried out on an LCQ Classic ducted at the General Clinical Research Unit (GCRC) of Finnigan LC-MS/MS system (ThermoFinnigan, San Jose, University of California, Los Angeles. Eleven (11) volun- CA), equipped with a HP 1100 series HPLC system consist- teers ages 25 to 45 year were recruited for the study. Writ- ing of an autosampler and injector, quaternary pump, column ten consent was obtained. All participants were in goodhealth according to medical history, physical examination,electrocardiogram, and clinical laboratory measurements (serum chemistry, liver function tests, and hematology).
Subjects were excluded if they were smokers, tobacco users,or taking any medication including over-the-counter med- ications within 14 days prior to the study.
This was an open label, randomized, crossover study with a 1-week washout period between two phases. The previousstudy had demonstrated that 2400 mg of CRYR is a rele- High performance liquid chromatography trace of mona- vant comparison dose to 20 mg of lovastatin for lowering colins. 1, Monacolin Kanalogue; 2, Monacolin K dehydro ana-
logue; 3, Hydroxy-acid form of Monacolin L; 4, Hydroxy-acid
form of Monacolin K; 5, Dihydromonacolin K; 6, Monacolin L;
Kantola et al.8 reported that grapefruit increased the 7, Hydroxy-acid form of dehydromonacolin K; 8, Monacolin K; 9,
serum levels of lovastatin (Cmax) approximately 12-fold and Methyl ester of hydroxy-acid form of monacolin K; 10, Dehy-
the area under the concentration-time curve (AUC) 15-fold LOVASTATIN VERSUS RED YEAST RICE
#143-147 RT: 0.78-0.80 AV: 5 NL: 1.74E6F: +p Full ms2 427.20@35.00[115.00-500.00] K acid #57 RT: 0.59 AV: 1 NL: 2.96E5T: −p Full ms2 421.30@30.00 [115.00-500.00] sim #72-74 RT: 0.38-0.40 AV: 3 NL: 1.53E6T: +p Full ms2 441.20@35.00 [120.00-500.00] MA); Solvent A) 0.5% acetic acid/acetonitrile, B) 0.5% acetic acid/water; binary linear gradient system: 0–15 min: 50% A in B to 90% A in B; 15–18 min, 90% A in B; flow rate 0.2 mL/minute; injection volume 20 L; column temperature 25°C. Mass spectrometer (MS) parameters: The MS (elec- trospray ionization; ESI) was operated in the negative mode for the first 11 minutes and then in the positive mode for the rest of the analytical run; scan range: 115–500 amu; scan rate: 1 scan/sec; cone voltage: 17 eV. Peak identities for lovastatin, lovastatin hydroxy-acid, and simvastatin were obtained by comparison of their LC-MS/MS ions with their standards.
Each C8 SPE cartridge was preconditioned with methanol (2 ϫ 1 mL) and water (2 ϫ 1 mL). Each plasma sample (400 L) was loaded onto the cartridge and allowed to free- flow by gravity. Each cartridge was then eluted with con- secutive aliquots of 1 mL water, 1 mL 5% formic acid, and then 1 mL of water. The cartridge was allowed to drip dry, left to stand for 1 minute, then eluted with 1 mL methanol:water (7:3 v/v) solution, and finally with 1 mL of acetoni- A. Liquid chromatography-mass spectrometry (LCMS)
trace of lovastatin (monacolin K) standard. The molecular ion is trile. The combined acetonitrile eluates were evaporated to at m/z 427 ϭ [M ϩ Na]ϩ as reported.9 B. LCMS trace of lovas-
dryness in vacuo at low temperature, reconstituted in the tatin (monacolin K) hydroxy-acid standard. The molecular ion at HPLC mobile phase (100 L), vortexed for 1 minute, and m/z 421 ϭ [M–H]Ϫ as reported.9 C. LCMS trace of simvastatin
injected onto the LC column for LC-MS analyses.
standard. The molecular ion is at m/z 441 ϭ [M ϩ Na]ϩ as re- Plasma calibration standards of lovastatin and its hy- droxy-acid were prepared by spiking control human plasmawith known concentrations of working solutions of the stan- heater, and diode array detector (DAD). Data handling was dards. Samples were processed according to the extraction carried out using Xcalibur 1.2 software (ThermoFinnigan).
procedure and injected on to the HPLC-MS. Concentrations Conditions for detection were as follows: Column, Symme- were determined from the peak area by using the equation try C-18, 100 mm ϫ 2.1 i.d., 3.5 m, (Waters Corp., Milford, for linear regression obtained from the calibration curve. The calibration curve was linear (R2 ϭ 0.9954 for lovastatin and 0.9927 for lovastatin hydroxy-acid, respectively) over the The mean values and pharmacokinetics for lovastatin and concentration range from 0.1 to 100 ng/mL. The lower level CRYR are summarized in Table 2 and the mean plasma con- of quantitation (LOQ) established from the calibration curve centration versus time profiles for monacolin K and mona- by LCMS was 0.1 ng/mL based on 400 L of plasma. Sim- colin K hydroxy-acid are shown in Figures 4A,B, respec- vastatin was used as an internal standard as previously re- tively. Monacolin K was detected in plasma 30 minutes after ingestion of either lovastatin or CRYR. The peak concen-tration reached at approximately 3 hours. The Cmax and AUC of lovastatin are 22.42 ng/mL, and 80.47 higher than CRYR The pharmacokinetic parameters, peak plasma concen- with p value of 0.001 and 0.002, respectively. The dose-nor- malized Cmax and AUC of lovastatin are 0.89 ϩ 0.22 ng/mL, max), time to peak plasma concentration (Tmax), and time for appearance of the drug in plasma were obtained and 3.41 ϩ 0.99 higher than CRYR with p value of 0.001 by observation. The AUC from 0 to 24 hours after dosing was calculated by the linear trapezoidal rule. Elimination Monacolin K hydroxy-acid was detected 30 minutes af- ter taking lovastatin or CRYR but peaked at 4 hours, 1 hour 1/2) was estimated by 0.693/, where is the ab- solute value of the slope of a least-square linear regression later than when monacolin K peaked. The Tmax for lovas- of plasma drug concentration (in natural logarithm scale) tatin and CRYR hydroxy-acids were similar (p ϭ 1.00, signed rank test). The Cmax for loavstatin hydroxy-acid is The pharmacokinetic parameters of lovastatin and lovas- 36.63 ng/mL higher than the Cmax of CRYR hydroxy-acid tatin hydroxy-acid were tabulated using mean Ϯ SEM for (p ϭ 0.001, signed rank test). The AUC of lovastatin hy- taking lovastatin and CRYR, respectively. This was a 2-by- droxy-acid is 258.5 larger than that of CRYR (p ϭ 0.001).
2 crossover study with 7-day washout period. No carryover After normalization for dose, the AUC of lovastatin is still effect was identified, and no significant period and sequence 7.21 larger than that of CRYR (p ϭ 0.001).
effects were found; therefore, signed rank test was used to The individual sample for minor monacolins were not de- compare the pharmacokinetic parameters for Lovastatin ver- tectable by LC-MS/MS. However, the pooled plasma sam- ples collected from three subjects showed the presence of All tests used were two sided with a significance level of minor monacolins reported to be present in CRYR.10 Sam- 0.05. Statistical software SAS was used to carry out theanalysis.
Characterization of the constituents of CRYR This botanical dietary supplement consists mainly of rice, and by-products of fermentation. The main groups of con- stituents are shown in Table 1. Clearly the most abundant ingredient is starch, constituting over 73% of the bulk. The protein content is 6%. The other ingredients are found in much less quantity. Trace elements were analyzed by atomic absorption spectroscopy. Magnesium is the most abundant metal with 1094 g/g of rice.
The typical HPLC trace for the monacolin mixture as found in CRYR is shown in Figure 1 and the Liquid Chro- matography—Mass Spectrometry (LC-MS) traces of mona- colin K, monacolin K hydroxyl-acid, and simvastatin stan- dards are shown in Figures 2A–C, respectively. Figure 3 shows the LC-MS trace of a plasma sample obtained froma human subject with simvastatin added as internal standard LCMS trace of human plasma sample showing mona- where monacolin K and monacolin K hydroxy-acid were de- colin K hydroxy-acid (tr ϭ 9.47 min, base peak m/z 319.06 frommolecular ion at m/z 421); Monacolin K (t tected. There is 1.23 mg of monacolin K in every capsule m/z 325.24 from molecular ion at m/z 427); Simvastatin (tr ϭ 14.46 by assay of manufacture and 1.15 mg by HPLC analyses min, base peak at m/z 325.12 from molecular ion at m/z 441.3) ac- LOVASTATIN VERSUS RED YEAST RICE
ples from all subjects were analyzed after pooled with two 429)ϩ, monacolin L (tR 13.28 min; M ϩ Na, m/z 327)ϩ, and subjects. All the analysis showed the same pattern of minor dehydromonacolin K (tR 18.90 min; M ϩ Na, m/z 409). Fig- monacolins. The data from one analysis are shown in Fig- ure 6B shows the LCMS trace of pooled plasma sample with ures 5 and 6. Because of the unavailability of standards for ions corresponding to dehydromonacolin K (tR 18.82 min; these minor monacolins, Selected Ion Monitoring (SIM) was conducted in negative and positive ESI modes of CRYR,and then followed by MS-MS analyses of ions correspond-ing to each monacolin peak (Figs. 5 and 6). Peak identities DISCUSSION
were obtained by matching their molecular ions (M Ϫ H)Ϫor (M ϩ Na)ϩ obtained by ES-MS/MS ions with expected In 1979, Endo11 reported that a strain of Monascus yeast values.10 Figure 5A shows the LCMS trace of the CRYR naturally produces a substance that inhibits cholesterol syn- extract in negative mode with corresponding MS/MS ions thesis, which he named monacolin K, as well as a family for monacolin K hydroxy-acid (tR 11.38 min; M Ϫ H m/z of eight monacolin-related substances with the ability to in- 421), dehydromonacolin K hydroxy-acid (tR 8.36 min; M Ϫ hibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) H m/z 403), monacolin L hydroxy-acid (tR 9.49 min; M Ϫ reductase. In addition to the inhibitors of HMG-CoA re- H m/z 321) and dihydromonacolin K hydroxy-acid (tR 14.10 ductase, red yeast rice has been found to contain sterols min; M Ϫ H m/z 423). Figure 5B shows the LCMS trace of (-sitosterol, campesterol, and stigmasterol), tannins, poly- the pooled human plasma sample with ions corresponding ketide pigments, sapogenin, isoflavones and isoflavone gly- to monacolin L hydroxy-acid (tR 9.49 min; M Ϫ H m/z 423) cosides, and monounsaturated fatty acids.11,12 and dihydromonacolin K hydroxy-acid (tR 14.09 min; M Ϫ CRYR has been shown to lower cholesterol in animals H m/z 423). Similarly, Figure 6A shows the LCMS trace of fed diets designed to induce hypercholesterolemia.13,14 In a the CRYR extract in positive mode with corresponding double-blind placebo-controlled and diet-controlled study, MS/MS ions for monacolin K (tR 14.47 min; M ϩ Na, m/z CRYR was demonstrated to lower serum cholesterol by 23% 427)ϩ, dihydromonacolin K (tR 17.26 min; M ϩ Na, m/z in 40 hypercholesterolemic patients compared to 40 patients A. Plasma concentration versus time profile for monacolin K. B. Plasma concentration versus time profile for monacolin K
A. Selected ion monitoring (SIM) spectra of the Chinese red yeast rice (CRYR) extract in negative mode with correspond-
ing MS/MS ions for monacolin K hydroxy-acid (tR 11.38 min; M Ϫ H m/z 421), dehydromonacolin K hydroxy-acid (tR 8.36 min; M Ϫ
H m/z 403), monacolin L hydroxy-acid (tR 9.49 min; M Ϫ H m/z 321), and dihydromonacolin K hydroxy-acid (tR 14.10 min; M–H m/z
423). B. SIM spectra of the pooled human plasma sample with corresponding MS/MS iosn for monacolin L hydroxy-acid (tR 9.49 min;
M–H m/z 321) and dihydromonacolin K hydroxy-acid (tR 14.09 min; M–H m/z 423).
15.32 15.70 16.03 16.59 17.42 17.94 18.37 19.08 19.72 14.66 15.19 15.82 16.24 16.7717.33 17.6917.9518.32 19.09 19.43 A. Selected ion monitoring (SIM) spectra of the Chinese red yeast rice (CRYR) extract in positive mode with corresponding
MS/MS ions for monacolin K (tR 14.47 min; M ϩ Naϩ, m/z 427), dihydromonacolin K (tR 17.26 min; M ϩ Naϩ, m/z 429), monacolin
L (tR 13.28 min; M ϩ Naϩ, m/z 327), and dehydromonacolin K (tR 18.90 min; M ϩ Naϩ, m/z 409). B. SIM spectra of pooled human
plasma sample with ion corresponding to dehydromonacolin K (tR 18.82 min; M ϩ Naϩ, m/z 409).
LOVASTATIN VERSUS RED YEAST RICE
given placebo.7 The monacolins in CRYR and drug statins were updated recently about pharmacologic intervention.
are competitive inhibitors of HMG CoA reductase, the reg- NCEP is now advocating more aggressive therapy for patients ulatory enzyme of cholesterol synthesis.15 with high and moderate risks.24 Although it is acknowledged The current study showed that the quantity of monacolin that side-effects with statins are rare, there are data indicat- K contained in CRYR is much lower and is inadequate to ing that some statins may cause liver function abnormalities explain the magnitude of cholesterol lowering observed in and, under certain circumstances, rhabdomyolysis in a dose- the previous study. The 2400 mg CRYR used in this study related fashion.25 Combined use of different statins in lower contains only 4.6 mg, 23% of monacolin K of 20 mg lo- doses may decrease the incidence of side-effects.
vastatin. The findings of this study demonstrated that theplasma concentrations of monacolin K and its hydroxy-acidform are much higher after ingestion of lovastatin than CONCLUSIONS
CRYR. The mixture of monacolins and other substances pre-sent in the red yeast rice may have some inhibitory effect In summary this study demonstrated significantly lower on cholesterol biosynthesis. Pooled plasma collected from serum monacolin K level for CRYR compared to equiva- three subjects showed the presence of additional minor lent cholesterol-lowering dose of lovastatin. CRYR may monacolins that are known to be present in red yeast rice.10 serve as a safe and effective natural alternative for people Various synthetic statins have different degrees of bio- with modest elevation of cholesterol. The effect of red yeast logic activity, and it is possible that the family of monacol- rice on the cholesterol concentration is not caused by mona- ins in CRYR may have a different profile of cellular or mol- colin K alone but the combination of monacolin K and other ecular actions. In the current study the monacolin K to monacolins, substances in the red yeast rice supplement.
monacolin K hydroxy-acid ratio was 1.72 for lovastatin and3.48 for CRYR, which further suggests possible differentmetabolism. At 72 hours after administration, approximately ACKNOWLEDGMENTS
83% of lovastatin was excreted in stool and 10% in urine.16Similar studies of the bioavailability and bioactivity of Funding was supplied by the PHS/Institute of National CRYR monacolins were not performed previously but would increase the understanding of the metabolism of thisbotanical dietary supplement.
Whereas the proprietary product used in this study was REFERENCES
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