Khvostov M.V., Tolstikova T.G., Dushkin A.V. and Tolstikov G.A.

Laboratory of Pharmacological Research. N.N. Vorozhtsov Institute of Organic Chemistry Siberian Branch of RAS. 630090, Russia, Novosibirsk, Acad. Lavrentjev Ave., 9

Abstract:

In the modern pharmacology and pharmaceutics a problem of toxicity and low water solubility of drugs is solving by different ways. Our approach is based on clathration of known drugs with plant metabolite arabinogalactan that is a polysaccharide contained in the woody tissue of the Siberian Larch (Larix sibirica) and the Dahurian Larch (Larix Gmelinii) and amounting to no less than 10%. This metabolite is currently actively researched, and its structure suggests the possibility of formation of clathrates with pharmacons. Clathrates of AG with the following drugs were synthesized and their pharmacological properties were studied in vivo: Nifedipine (NF), Simvastatin (ST), Warfarin (WF), Acetylsalicylic acid (AA).
All clathrates were synthesized using the mechanochemical method at the Institute of Solid State Chemistry and Mechanochemistry SB RAS.

It was found that for all those drugs the clathration with AG results in significant increase (up to 7 times) in water solubility. In the case of Nifedipine we have achieved 10 times dose reduction and enhancement of its pleotropic antiarhythmic activity. Simvastatin and Warfarin in clathrate possess considerably low toxicity, i.e. do not elevate aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase and creatine phosphokinase (just for ST) levels as blank compounds do. Moreover the pharmacokinetics of clathrated WF is also has been changed. Its plasma concentration increased more smoothly (Tmax) than concentration of blank WF but its clearance value was shorter to 27%. It could be resulted in reduction of bleeding risk caused by rapid increase of WFs plasma concentration during the induction period of WF treatment and could secure repeat dosing and accelerate WFs elimination in case of drug withdrawal.