Arch Med Sci. 2015 Apr 25;11(2):406-10.

Improvement of hepatic bioavailability as a new step for the future of statins.

Petyaev IM.

Lycotec Ltd, Granta Park Campus, Cambridge, CB21 6GP, United Kingdom.

 

Abstract

Statins (HMG-CoA reductase inhibitors) are a group of highly efficient pharmacological agents used for reducing blood cholesterol level and prevention/treatment of cardiovascular disease. Adverse reactions during statin treatment affect quite significant numbers of patients (reportedly from 5% to 20%), with more side effects occurring at higher doses. Reduced statin dosing can be achieved by improved bioavailability of statins, which is fairly low due to poor aqueous solubility, low permeability and high molecular weight of some members of the statin family. Moreover, since hepatic cholesterologenesis is a main target of statin action and extrahepatic inhibition of HMG-CoA reductase has no effect on plasma lipids, hepatic bioavailability, in our opinion, becomes a new important modality of statins maximizing their potential effect on the plasma lipid profile and diminishing their extrahepatic toxicity. Therefore efficient delivery systems of statins into hepatocytes need to be developed and introduced. Uses of nano-emulsifying statin delivery systems which may include vectors of intrahepatic transport, in particular lycopene, are discussed. As a proof of concept, some preliminary results revealing the effect of a lycopene-containing nanoformulation of simvastatin (designated as Lyco-Simvastatin) on LDL in mildly hypercholesterolemic patients are shown.

PMID: 25995759

 

Supplement:

Statins (HMG-CoA reductase inhibitors), the best selling drugs in modern history, are used for the treatment of hypercholesterolemia as well as prevention of atherosclerosis and cardiovascular disease. As a class of pharmacological substances, statins target the cholesterol biosynthesis pathway in liver, a main organ of cholestrologenesis in the human body. However, the action of statins is not limited to the liver and oral statin intake has undesirable consequences for extrahepatic tissues. Minimizing exposure of extrahepatic tissues to the statins becomes extremely important due to reports revealing toxic effects of HMG-CoA reductase inhibitors on different organs and tissues, especially skeletal muscle. Reduced dosing of statins as a single measure cannot resolve the problem of extrahepatic toxicity, since many patients placed on the minimized statin treatment schedule are not able to achieve necessary goals in cholesterol reduction. Therefore, targeted delivery of statins to the liver becomes an important task of modern pharmacotherapy. Hepatoselectivity of statins may constitute a new and extremely desirable characteristic of statins.

Most of statins are lipophilic substances with poor intestinal absorption rates. Thus the microencapsulation approach might be an effective way to promote gastrointestinal uptake of statins. With this in mind, we applied lycosome technology (1) for microencapsulation of statins, in particular simvastatin (Lycosimvastatin).

Lycosomes are nanoparticles with average size of 100 nm. Preparation of lycosomes includes spray drying, application of ultrasound and supercritical CO2.

 

IP FIG1

Figure 1.  Lycosome Structure

 

The encapsulated portion of the particles contains lipophilic compound of interest (in this particular case – Simvastatin) surrounded by phosphatidylcholine used here as chaperone. Exposed layer is represented by lycopene and polar heads of phosphatidylcholine. Lycopene particles are partially resistant to acidic environment of stomach and can be absorbed in unmodified form.

In a pilot clinical trial, which involved 10 mildly hypercholesterolemic patients, we compared the clinical efficacy of lycosome-formulated Simvastatin (Lycosimvastatin) versus unmodified Simvastatin. Both formulation were taken during a month period, once a day in the amount of 20 mg. As we reported, Lycosimvastatin caused more significant reduction of LDL cholesterol in plasma as compared to unmodified drug. This decrease was also accompanied by reduction in ApoB level.

 

IP FIG2

Figure 2. Changes in ApoB Levels

 

To disclose the nature of this phenomenon we conducted some animal experiments in collaboration with the Institute of Microbiology (Moscow, Russian Federation). We have found that feeding of rats with lycosome formulated Simvastatin leads to higher accumulation of drug in the hepatic tissue as compared to unmodified drug.

 

IP FIG3

Figure 3. Accumulation of Simvastatin in Rat Liver

 

Thus, microencapsulation promotes hepatic delivery of statins upon oral ingestion.

In our opinion, presence of lycopene in the lycosome structure confers hepatoselectivity to Lycosimvastatin. Lycopene is considered to be a powerful ligand to the receptors participating in carotenoid uptake in liver. As we have shown previously, lycosome can be efficiently incorporated into chylomicrons and enter hepatocytes via ApoB-mediated mechanisms. Therefore microencapsulation of simvastatin into microparticles coated with lycopene, a ligand of intrahepatic delivery, allows better pharmacological effect of the drug due to improved delivery of simvastatin into hepatocytes. Use of lycosome-formulated statins may allow reduction in statin dosage as well as decrease the risk of undesirable side effects of statins without compromising outcomes of the cholesterol-lowering pharmacotherapy.

 

REFERENCES

  1. Carotenoid Particles And Uses Thereof. GB Patent Application No. 1101669.8, PCT/GB2012/000075, 25.01.2012.

 

IP FIG4

Ivan M Petyaev MD, PhD

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