Bile acid/fatty acid integrated nanoemulsomes for nonalcoholic fatty liver targeted lovastatin delivery: stability, in-vitro, ex-vivo, and in-vivo analyses.

BACKGROUND: Controlled and targeted drug delivery to treat nonalcoholic fatty liver disease (NAFLD) can benefit from additive attributes of natural formulation ingredients incorporated into the drug delivery vehicles. METHODS: Lovastatin (LVN) loaded, bile acid (BA) and fatty acid (FA) integrated nanoemulsomes (NES) were formulated by thin layer hydration technique for synergistic and targeted delivery of LVN to treat NAFLD. Organic phase NES was comprised of stearic acid with garlic (GL) and ginger (GR) oils, separately. Ursodeoxycholic acid and linoleic acid were individually incorporated as targeting moieties. RESULTS: Stability studies over 90 days showed average NES particle size, surface charge, polydispersity index, and entrapment efficiency values of 270 ± 27.4 nm, -23.8 ± 3.5 mV, 0.2 ± 0.04 and 81.36 ± 3.4%, respectively. Spherical NES were observed under a transmission electron microscope. In-vitro LVN release depicted non-fickian release mechanisms from GL and GR oils-based NES. Ex-vivo permeation of BA/FA integrated NES through isolated rat intestines showed greater flux than non-integrated ones. CONCLUSION: Liver histopathology of experimental rats together with in-vivo lipid profiles and liver function tests illustrated that these NES possess the clinical potential to be promising drug carriers for NAFLD.

Prescription of statins and pharmacokinetic interactions in Colombian patients.

Background: Statins have extensive hepatic metabolism and can have multiple pharmacological interactions. The aim was to identify the main pharmacokinetic interactions between statins and their comedications in a group of patients from Colombia.Research design and methods: A cross-sectional study of pharmacokinetic interactions in patients treated with statins who were identified from a population database. The interactions were documented using the Lexicomp® database.Results: A total of 123,026 patients with statin prescriptions were identified, with a mean age of 68.4 ± 11.5 years; 57.1% were women, and 81.6% received atorvastatin. A total of 19.4% (n = 23.831) of patients presented pharmacological interactions. Some 15,474 (12.6%) had interactions classified as category C, 7.4% (n = 9077) as category D, and 0.5% (n = 660) as category X. 36.8% of the patients with lovastatin prescriptions had some interaction. Age older than 65 years, male sex, residence in capital cities, comorbidities, endocrine pathologies and HIV were associated with an increase in the probability of having contraindicated or risky interactions.Conclusions: Important interactions between statins and other medications were more common in adults over 65 years of age and those with endocrine comorbidities or HIV infection. This knowledge should help when proposing solutions that reduce the risk of adverse reactions.

Preparation, Characterization and in vitro/in vivo Evaluation of Lovastatin-Loaded PLGA Microspheres by Local Administration for Femoral Head Necrosis.

BACKGROUND: The present work is an effort to develop a novel locally injection LVTT-loaded PLGA microspheres (LVTT-PLGA-MS) on the treatment of rabbits with femoral head necrosis (FHN). METHODS: LVTT-loaded PLGA microspheres (LVTT-PLGA MS) were prepared by an emulsion-solvent evaporation method. The physicochemical properties of LVTT-PLGA-MS were investigated to ensure that they have good qualities and are suitable for local delivery. In vitro drug release behavior of MS was also studied compared with free LVTT. In vivo, we also studied the pharmacokinetics and pharmacodynamics of MS in rabbits with the optimized formulation. RESULTS: In this study, we used the emulsion-solvent evaporation method to prepare LVTT-PLGA MS. Scanning electron microscopy demonstrated that the LVTT-PLGA MS were regular, round in shape and relatively unified size distributions were selected. The mean PS was 12.3±2.1 µm. The drug-loading rate (27.6% ± 2.9%) was calculated for three batches of MS. The thermogram of LVTT-PLGA MS showed an endothermic peak at 98.3°C, revealing that LVTT existed in MS in an uncrystallized rather than a crystallized form. In the release study, LVTT-PLGA MS is observed linear prolonging drug release rates for more than 21 days without initial burst release. The pharmacodynamic results confirmed that the LVTT-PLGA MS had a good and lasting improvement effect against femoral head necrosis. CONCLUSION: Our results demonstrated that LVTT-PLGA MS has the potential for being a local delivery system.

Development of One Pot Strategy for Hyper Production and In Vivo Evaluation of Lovastatin.

The aim of this project was to improve the Aspergillus terreus strain and pretreatment of sugarcane bagasse as carrier substrate for bulk production of lovastatin, a cholesterol-lowering drug, in solid state fermentation. Sugarcane bagasse was treated with alkali (1-3% NaOH) for the conversion of complex polysaccharides into simple sugars for better utilization of carrier substrate by microorganism for maximum lovastatin production. Ethidium bromide (time of exposure 30-180 min) was used to induce mutation in Aspergillus terreus and the best mutant was selected on the basis of inhibition zone appeared on petri plates. Fermented lovastatin was quantified by high-performance liquid chromatography. The fermented lovastatin, produced by parent and mutant Aspergillus terreus strain, was checked on body weight, blood glucose and serum cholesterol, ALT, AST, HDL-C, LDL-C, TG and TC levels of rats for their cholesterol lowering capacity. Our results indicate that selected strain along with 2% NaOH treated sugar cane bagasse was best suitable for bulk production of lovastatin by fermentation and fermented lovastatin effectively lower the cholesterol level of rats.

Nanoparticles of Lovastatin: Design, Optimization and in vivo Evaluation.

INTRODUCTION: The aim of the study was to optimize the processing factors of precipitation-ultrasonication technique to prepare nano-sized particles of Lovastatin (LA) for enhancing its solubility, dissolution rate and in vivo bioavailability. METHODS: LA nanoparticles (LANs) were prepared using precipitation-ultrasonication technique under different processing factors. LANs were characterized in terms of particle size, zeta potential and in vitro release. Stability studies at 4°C, 25°C and 40°C were conducted for optimum formulation. In addition, the in vivo bioavailability of the optimum formula was studied in comparison to a marketed product in white master rats. RESULTS: The optimized LAN formula (LAN15) had particle size (190±15), polydispersity index (0.626±0.11) and a zeta potential (-25±1.9 mV). The dissolution study of the nanosuspensions showed significant enhancement compared with pure drug. After 50 min, only 20.12±1.85% of LA was dissolved while 99.1±1.09% of LA was released from LAN15. Stability studies verified that nanosuspensions at 4°C and 25°C showed higher stability with no particle growth compared to the samples studied at 40°C. In vivo studies conducted in rats verified that there was 1.45-fold enhancement of Cmax of LAN15 as compared to marketed tablets. CONCLUSION: Nanoparticle prepared by ultrasonication-assisted precipitation method is a promising formula for enhancing the solubility and hence the bioavailability of Lovastatin.

An assessment of bioavailability of acrylate based pH-sensitive complexes of lovastatin.

Lovastatin (LSN), a potent anti-hyperlipidemic drug, possesses poor bioavailability due to its very low aqueous solubility. The objective of this study was to establish a relationship between increased drug solubility before reaching site of absorption or increasing drug solubility at target absorption site for accentuated bioavailability of LSN. Composites of LSN with oppositely natured pH-sensitive acrylate polymers, cationic Eudragit EPO (EPO) and anionic Eudragit L100 (L100), were fabricated with physical trituration and kneading methods. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM, dissolution and bioavailability studies in rats. Interestingly, we observed that physical mixtures of EPO outmatched its kneaded formulations, whereas the physical mixtures and kneaded dispersions of L100 were virtually similar in characteristics. EPO was superior in boosting LSN solubility in the respective medium than the L100. Moreover, EPO produced immediate release profile in gastric environment whereas L100 offered sustained release of LSN in intestinal milieu. Bioavailability studies in rats further supported the EPO formulation in terms of shorter Tmax, higher Cmax and heightened AUC.

Impacts of particle shapes on the oral delivery of drug nanocrystals: Mucus permeation, transepithelial transport and bioavailability.

For drug nanocrystals (NCs), particle shapes can affect aqueous solubility, dissolution rate and oral bioavailability. However, the effects of particle shapes on the transport of NCs across the intestinal barriers remain unclear. In the present study, spherical, rod-shaped and flaky NCs (SNCs, RNCs, and FNCs) were prepared and characterized. Meanwhile, fluorescence resonance energy transfer molecules were used to track the fate of intact NCs. Results showed that particle shapes had great influences on the mucus permeation, cellular uptake and transmembrane transport of NCs, and RNCs exhibited the best absorption efficiency. Besides, we found that endoplasmic reticulum/Golgi and Golgi/plasma membrane pathways might be involved in the transcytosis and exocytosis of NCs. Moreover, the oral bioavailability study showed that AUC0-24h of RNCs was 1.44-fold and 1.8-fold higher than that of SNCs and FNCs, respectively. Collectively, these results provided compelling evidences that RNCs could potentially improve the absoption efficacy of NCs in oral delivery. Our findings give deep insights into the impacts of particle shapes on the oral absoption of NCs and provide valuable knowledge for rational design of optimized NCs for oral drug delivery.

Rational Design of Lovastatin-Loaded Spherical Reconstituted High Density Lipoprotein for Efficient and Safe Anti-Atherosclerotic Therapy.

Reconstituted high density lipoprotein (rHDL) is a biomimetic nanoparticle with plaque targeting and anti-atherosclerotic efficacy. In this work, we report on a strategy to rational design of lovastatin (LOV)-loaded spherical rHDL (LOV-s-rHDL) for efficient and safe anti-atherosclerotic therapy. Briefly, three LOV-s-rHDLs were formulated with LOV/s-rHDL at ratios of 8:1, 10:1, and 15:1 upon their respective median-effect values ( Dm). The combined inhibitory effect between LOV and s-rHDL of different LOV-s-rHDL formulations on DiI-labeled oxLDL internalization was systemically investigated in RAW 264.7 cells based on the median-effect principle. Median-effect analysis demonstrated that the optimized LOV-s-rHDL was formulated with a ratio of 10:1 ( Dm LOV: Dm s-rHDL), in which LOV and s-rHDL carrier showed the best synergistic effect, presumably ascribed to their inhibitory effect on CD36 and SR-A expression according to the Western blot analysis. In vivo pharmacodynamics studies showed that the optimized LOV-s-rHDL displayed the most pronounced anti-atherosclerotic effect on decreasing plaque area and reducing the MMP level following an 8-week dosing regimen. In vivo atherosclerotic plaque targeting analysis revealed that s-rHDL had potent plaque targeting efficacy, probably owing to the interaction between apoA-I and scavenger receptor B-I. Furthermore, we observed that the optimized LOV-s-rHDL exhibited a favorable safety profile as evidenced by the results of a hemolysis assay, cell cytotoxicity study, and in vivo safety test. Collectively, the rational design of the biomimetic LOV-s-rHDL based on the median-effect analysis provides an efficient strategy to achieve a synergistic and safe anti-atherosclerotic therapy.

Analysis of a Skeletal Muscle Injury and Drug Interactions in Lovastatin- and Fenofibrate-Coadministered Dogs.

Because dogs are widely used in drug development as nonrodent experimental animals, using a dog model for drug-induced adverse reactions is considered to be relevant for an evaluation and investigation of a mechanism and a biomarker of clinical drug-induced adverse reactions. Skeletal muscle injury occurs by various drugs, including statins and fibrates, during drug development. However, there is almost no report of a dog model for drug-induced skeletal muscle injury. In the present study, we induced skeletal muscle injury in dogs by oral coadministration of lovastatin (LV) and fenofibrate (FF) for 4 weeks. Increases in plasma levels of creatine phosphokinase, myoglobin, miR-1, and miR-133a and degeneration/necrosis of myofibers in skeletal muscles but not in the heart were observed in LV- and FF-coadministered dogs. Plasma levels of lovastatin lactone and lovastatin acid were higher in LV- and FF-coadministered dogs than LV-administered dogs. Taken together, FF coadministration is considered to affect LV metabolism and result in skeletal muscle injury.

Unremarkable impact of Oatp inhibition on the liver concentration of fluvastatin, lovastatin and pitavastatin in wild-type and Oatp1a/1b knockout mouse.

1. Oatp inhibitors have been shown to significantly increase the plasma exposure of statins. However, understanding alterations of liver concentration is also important. While modeling has simulated liver concentration changes, availability of experimental data is limited, especially when concerning drug-drug interactions (DDI). The objective of this work was to determine blood and liver concentrations of fluvastatin, lovastatin and pitavastatin, when blocking uptake transporters. 2. In wild-type mouse, rifampin pre-treatment decreased the unbound liver-to-plasma ratio (Kp,uu) of fluvastatin by 4.2-fold to 2.2, lovastatin by 4.9-fold to 0.81 and pitavastatin by 10-fold to 0.21. Changes in Kp,uu were driven by increases in systemic exposures as liver concentrations were not greatly altered. 3. In Oatp1a/1b knockout mouse (KO), rifampin exerted no additional effect on fluvastatin and lovastatin. Contrarily, rifampin further decreased pitavastatin Kp,uu by 3.4-fold, suggesting that the KO is inadequate to completely block liver uptake of pitavastatin as there are additional rifampin-sensitive uptake mechanism(s) not captured in the KO model. 4. This work provides experimental data showing that the plasma compartment is more sensitive to Oatp modulation than the liver compartment, even for rifampin-mediated DDI. Consistent with previous simulations, inhibiting or targeting Oatps may change Kp,uu, but exhibit only a minimal effect on absolute liver concentrations.

Interaction of statins with phospholipid bilayers studied by solid-state NMR spectroscopy.

Statins are drugs that specifically inhibit the enzyme HMG-CoA reductase and thereby reduce the concentration of low-density lipoprotein cholesterol, which represents a well-established risk factor for the development of atherosclerosis. The results of several clinical trials have shown that there are important intermolecular differences responsible for the broader pharmacologic actions of statins, even beyond HMG-CoA reductase inhibition. According to one hypothesis, the biological effects exerted by these compounds depend on their localization in the cellular membrane. The aim of the current work was to study the interactions of different statins with phospholipid membranes and to investigate their influence on the membrane structure and dynamics using various solid-state NMR techniques. Using 1H NOESY MAS NMR, it was shown that atorvastatin, cerivastatin, fluvastatin, rosuvastatin, and some percentage of pravastatin intercalate the lipid-water interface of POPC membranes to different degrees. Based on cross-relaxation rates, the different average distribution of the individual statins in the bilayer was determined quantitatively. Investigation of the influence of the investigated statins on membrane structure revealed that lovastatin had the least effect on lipid packing and chain order, pravastatin significantly lowered lipid chain order, while the other statins slightly decreased lipid chain order parameters mostly in the middle segments of the phospholipid chains.

Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules.

Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.

Evaluation of the Combined Effect of Recombinant High-Density Lipoprotein Carrier and the Encapsulated Lovastatin in RAW264.7 Macrophage Cells Based on the Median-Effect Principle.

Recombinant high-density lipoprotein (rHDL) displays a similar anti-atherosclerotic effect with native HDL and could also be served as a carrier of cardiovascular drug for atherosclerotic plaque targeting. In our previous studies, rHDL has shown a more potent anti-atherosclerotic efficacy as compared to the other conventional nanoparticles with a payload of lovastatin (LS). Therefore, we hypothesized that a synergistic anti-atherosclerotic effect of the rHDL carrier and the encapsulated LS might exist. In this study, the dose-effect relationships and the combined effect of the rHDL and LS were quantitatively evaluated in RAW 264.7 macrophage cells using the median-effect analysis, in which the rHDL carrier was regarded as a drug combined. Median-effect analysis suggested that rHDL and LS exerted a desirable synergistic inhibition on the oxLDL internalization at a ratio of 6:1 ( Dm,LS: Dm,rHDL) in RAW 264.7 macrophage cells. About 50% of the reduction on the intracellular lipid contents was found when RAW264.7 cells were treated with LS-loaded rHDLs at their respective median-effect dose ( Dm) concentrations and a synergistic effect on the mediating cholesterol efflux was also observed, which verified the accuracy of the results obtained from the median-effect analysis. The mechanism underlying the synergistic effect of the rHDL carrier and the drug might be attributed to their potent inhibitory effects on SR-A expression. In conclusion, the median-effect analysis was proven to be a feasible method to quantitatively evaluate the synergistic effect of the biofunctional carrier and the drug encapsulated.

Controlled release of lovastatin from poly(lactic-co-glycolic acid) nanoparticles for direct pulp capping in rat teeth.

Statin at appropriate concentrations has been shown to induce odontoblastic differentiation, dentinogenesis, and angiogenesis. However, using a carrier to control statin release might reduce toxicity and enhance its therapeutic effects. The aim of this study was to prepare poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles that contain lovastatin for application in direct pulp capping. The PLGA-lovastatin particle size was determined using dynamic light scattering measurements and transmission electron microscopy. In addition, the release of lovastatin was quantified using a UV-Vis spectrophotometer. The cytotoxicity and alkaline phosphatase (ALP) activity of PLGA-lovastatin nanoparticles on human dental pulp cells were investigated. Moreover, a real-time polymerase chain reaction (PCR) assay, Western blot analysis, and an enzyme-linked immunosorbent assay (ELISA) were used to examine the osteogenesis gene and protein expression of dentin sialophosphoprotein (DSPP), dentin matrix acidic phosphoprotein 1 (DMP1), and osteocalcin (OCN). Finally, PLGA-lovastatin nanoparticles and mineral trioxide aggregate (MTA) were compared as direct pulp capping materials in Wistar rat teeth. The results showed that the median diameter of PLGA-lovastatin nanoparticles was 174.8 nm and the cumulative lovastatin release was 92% at the 44th day. PLGA-lovastatin nanoparticles demonstrated considerably a lower cytotoxicity than free lovastatin at 5, 9, and 13 days of culture. For ALP activity, the ALP amount of PLGA-lovastatin (100 µg/mL) was significantly higher than that of the other groups for 9 and 13 days of culture. The real-time PCR assay, Western blot analysis, and ELISA assay showed that PLGA-lovastatin (100 µg/mL) induced the highest mRNA and protein expression of DSPP, DMP1, and OCN in pulp cells. Histological evaluation of the animal studies revealed that MTA was superior to the PLGA-lovastatin in stimulating the formation of tubular dentin in an observation period of 2 weeks. However, in an observation period of 4 weeks, it was evident that the PLGA-lovastatin and MTA were competitive in the formation of tubular reparative dentin and a complete dentinal bridge.

Development of enteric-coated fixed dose combinations of amorphous solid dispersions of ezetimibe and lovastatin: Investigation of formulation and process parameters.

Enteric-coated fixed-dose combinations of ezetimibe and lovastatin were prepared by fluid bed coating aiming to avoid the acidic conversion of lovastatin to its hydroxyacid derivative. In a two-step process, sucrose beads were layered with a glass solution of ezetimibe, lovastatin and Soluplus®, top-coated with an enteric layer. The impact of different bead size, enteric polymers (Eudragit L100® and Eudragit L100-55®) and coating time was investigated. Samples were evaluated by X-ray diffraction, scanning electron microscopy, laser diffraction and in vitro studies in 0.1M HCl and phosphate buffer pH 6.8. Results showed that smaller beads tend to agglomerate and release was jeopardized in acidic conditions, most likely due to irregular coating layer. Eudragit L100-55® required longer processing, but thinner coating layers provided lower drug release. Both polymers showed low drug release in acidic environment and fast release at pH 6.8. The off-line measurement of the coating thickness determined the ideal coating time as 15 and 30min for Eudragit L100-55® and Eudragit L100®-based samples, respectively. Both compounds were molecularly dispersed in Soluplus®, and Eudragit L100® formulations showed concave pores on the surface, presenting higher drug release in acidic conditions. Stability studies after 6 months showed unaltered physical properties and drug release.

Effect of polymorphisms in CYP3A4, PPARA, NR1I2, NFKB1, ABCG2 and SLCO1B1 on the pharmacokinetics of lovastatin in healthy Chinese volunteers.

AIM: This study examined whether gene polymorphisms (CYP3A4, ABCG2, SLCO1B1, NR1I2, PPARA and NFKB1) influenced the pharmacokinetics of lovastatin in Chinese healthy subjects. PATIENTS & METHOD: Plasma concentrations of lovastatin and lovastatin acid were quantified using LC/MS/MS. RESULTS: PPARA c.208+3819 G allele carriers had approximately twofold higher AUC0-∞ and Cmax of lovastatin than wild-type (PPARA c.208+3819 AA) subjects. After adjustment for the PPARA variants, subjects with the SLCO1B1 521TT genotype had approximately 50% lower AUC0-∞ of lovastatin acid than those with 521TC/CC genotypes, while the AUC0-∞ of lovastatin lactone in NFKB1-94 DD wild-type carriers was twofold higher than in mutant homozygotes carriers. CONCLUSION: Gene polymorphisms of PPARA, SLCO1B1 and NFKB1 affected the pharmacokinetics of lovastatin.

Simultaneous determination of lovastatin and its metabolite lovastatin acid in rat plasma using UPLC-MS/MS with positive/negative ion-switching electrospray ionization: Application to a pharmacokinetic study of lovastatin nanosuspension.

Lovastatin (LOV) is an antihyperlipidemic agent which exhibits low bioavailability due to its poor solubility. Therefore, a nanosuspension (NS) was developed as an efficient strategy to improve its oral bioavailability. To evaluate the pharmacokinetics of LOV-NS, a novel, sensitive, and rapid UPLC-MS/MS method was developed and validated for the simultaneous determination of LOV and its metabolite lovastatin acid (LOVA) in rat plasma. Simvastatin (IS) was chosen as the internal standard, and a liquid-liquid extraction method was used to isolate LOV and LOVA from biological matrices. The analytes were analyzed on an Acquity UPLC BEH C18 column, and a gradient program was applied at a flow rate of 0.2mL/min. Then, a tandem quadrupole mass spectrometer coupled with a positive/negative ion-switching electrospray ionization interface was employed to detect the analytes. Quantitation of the analytes was performed in the multiple reaction monitoring mode to monitor the transitions of m/z 427.1→325.0 for LOV and m/z 441.1→325.0 for IS in the positive ion mode and m/z 421.0→101.0 for LOVA in the negative ion mode, respectively. The method was validated over the concentration range 0.25-500ng/mL (r(2)≥0.99) for both LOV and LOVA. The intra-day and inter-day precision (RSD%) of LOV and LOVA were less than 12.87% and the accuracy (RE%) was less than 5.22%. The average extraction recoveries were 90.1% and 91.9% for LOV and LOVA, and the matrix effects were found to be between 85% and 115%. The stability study showed that both analytes were stable during the experiment. Finally, this method has been successfully applied to a pharmacokinetic study in rats following a single oral dose of 10mg/kg LOV-NS.

In Vivo and in Vitro Study on Drug-Drug Interaction of Lovastatin and Berberine from Pharmacokinetic and HepG2 Cell Metabolism Studies.

BACKGROUND: We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine. METHODS: An UPLC-MS/MS method was developed and validated for the pharmacokinetics tudy of lovastatin to investigate the in vivo drug-drug interactions between lovastatin and berberine. SD male rats were random divided into lovastatin group and berberine induced prior to lovastatin group for the in vivo pharmacokinetic studies. Meanwhile HepG2 cells were induced by berberine for three days to study the metabolism of lovastatin. RESULTS: The AUC (p < 0.01) and Cmax (p < 0.01) could be significantly decreased in the berberine-induced group in vivo, and the metabolic activity of HepG2 cell ccould be increased by berberine induction in vitro. The metabolism parameters of lovastatin such as CL, Vmax and Km were increased after the induction of berberine. From the pharmacokinetic study of lovastatin induced with berberine, we obtained pharmacokinetic parameters which are compliance with the metabolic parameters of lovastatin in HepG2 cells with berberine induction in vitro. CONCLUSIONS: From the in vivo pharmacokinetics study and the HepG2 cell metabolism study in vitro, berberine could be an inducer for the metabolism of lovastatin according to our previous research on berberine induction effects on HepG2 cells, which may be relevant to the fact that berberine possesses induction effects through the CYP 450 3A4 enzyme.