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.

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.

Bama miniature pigs (Sus scrofa domestica) as a model for drug evaluation for humans: comparison of in vitro metabolism and in vivo pharmacokinetics of lovastatin.

The objective of this study was to demonstrate that Bama miniature pigs are a suitable experimental animal model for the evaluation of drugs for man. To this end, in vitro lovastatin metabolism at the minipig liver microsomal level and in vivo pharmacokinetics were studied. Results were compared with those obtained from humans. Our data indicate that the main metabolites and enzyme kinetic parameters of lovastatin metabolism are similar in pigs and humans. Triacetyloleandomycin, a specific inhibitor of human CYP3A4, inhibited the metabolism of lovastatin in pig and human liver microsomes. In addition, the pharmacokinetic parameters and absolute bioavailability suggested that the absorption and elimination of lovastatin in Bama miniature pigs were similar to those in humans. Lovastatin was distributed across many organs in pigs, but the highest levels were found in the stomach, intestines, and liver. Within 96 h, 7% and 82% of the given dose was excreted in the urine and feces, respectively. In addition, no significant species differences in the plasma protein binding ratio of lovastatin and the rates of lovastatin hydrolysis to beta-hydroxyacid lovastatin were apparent. From these results, we conclude that Bama miniature pigs are suitable for use in drug evaluation studies.

Preparation, characterization, and in vitro and in vivo evaluation of lovastatin solid lipid nanoparticles.

The purpose of this research was to study whether the bioavailability of lovastatin could be improved by administering lovastatin solid lipid nanoparticles (SLN) duodenally to rats. Lovastatin SLN were developed using triglycerides by hot homogenization followed by ultrasonication. Particle size and zeta potential were measured by photon correlation spectroscopy. The solid state of the drug in the SLN and lipid modification were characterized. Bioavailability studies were conducted in male Wistar rats after intraduodenal administration of lovastatin suspension and SLN. Stable lovastatin SLN having a mean size range of 60 to 119 nm and a zeta potential range of -16 to -21 mV were developed. More than 99% of the lovastatin was entrapped in the SLN. Lovastatin was dispersed in an amorphous state, and triglycerides were in beta(1) form in the SLN. In vitro stability studies showed the slow release and stability of lovastatin SLN. The relative bioavailabilities of lovastatin and lovastatin hydroxy acid of SLN were increased by ~173% and 324%, respectively, compared with the reference lovastatin suspension.

Plasma clearance of lovastatin versus chinese red yeast rice in healthy volunteers.

OBJECTIVES: It is now accepted that inhibition of cholesterol biosynthesis is effective in the primary and secondary prevention of heart disease. However, the perceived side-effects on muscle and liver reduce the general acceptance of statin drug therapy as well as compliance over the long term, which is necessary for prevention efforts 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 double- blind placebo-controlled trial of CRYR supplement in 80 individuals demonstrating a significant decrease in cholesterol levels from 250 mg/dL to 210 mg/dL over 8 weeks independent of diet. The current study compared 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 20 mg of lovastatin. RESULTS: The Cmax and area under the curve (AUC) of lovastatin were 22.42 ng/mL, and 80.47 higher than CRYR (p = 0.001 and 0.002, respectively). The Cmax for lovastatin hydroxy-acid was 36.63 ng/mL higher than the Cmax of CRYR hydroxy-acid (p = 0.001). The AUC of lovastatin hydroxy-acid was 258.5 greater than that of CRYR (p = 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. It may lead to the ultimate development of a botanical supplement based on CRYR.

Preclinical and clinical pharmacology of cerivastatin.

Cerivastatin, a new, entirely synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is pharmacologically potent and hepatically selective, with an uncomplicated pharmacokinetic profile. In vitro and acute in vivo studies in animals demonstrated that cerivastatin is markedly more pharmacologically potent than other statins. In rats and dogs, cerivastatin inhibited hepatic cholesterol synthesis at concentrations 100-150 times lower than lovastatin. Cerivastatin's potent inhibition of HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis) is confirmed by its cholesterol-lowering properties, combined with significant triglyceride-decreasing effects, and dose-dependent increases in low-density lipoprotein (LDL) receptor binding in the liver. The antiatherogenic effects of cerivastatin extend beyond serum lipid and lipoprotein reductions to potent inhibition of migration of smooth muscle cells in vitro and reductions in the accumulation of cholesterol ester in the arterial tissue of rabbits. The high pharmacologic potency of cerivastatin, coupled with high liver selectivity, enable cerivastatin to be administered at 1-5% of the dose of currently available HMG-CoA reductase inhibitors. At ultra-low doses in the range 0.01-0.8 mg/day, cerivastatin proved to be both safe and well tolerated when administered to healthy volunteers in a series of ascending single- and multiple-dose studies. Cerivastatin has an uncomplicated pharmacokinetic profile; it can be administered to both young and elderly patients, male and female, without the need for dosage adjustments. Because no clinically significant pharmacokinetic drug interactions occur with cerivastatin, it may be the preferred HMG-CoA reductase inhibitor for patients on multiple-drug therapy including warfarin and digoxin.

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin.

AIMS: The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied. METHODS: Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. RESULTS: Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1) (mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase. CONCLUSIONS: Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.