Differences in bioavailability and cognitive-enhancing activity exerted by different crystal polymorphs of latrepirdine (Dimebon®)

Abstract

Introduction: Pharmacokinetic characteristics as well as cognitive-enhancing nootropic activity of latrepirdine (Dimebon®) in relationship with its polymorphic forms have been studied in SD and Wistar rats.Methods: The pharmacokinetics of six polymorphs (A, B, C, D, E, F) of latrepirdine were studied in male SD rats after 7 days of oral administration in corn oil at a dose of 10 mg/kg once a day. Blood and brain samples were taken on the 7th day of administration at 15 min, 30 min, 60 min and 120 min after administration and analyzed for latrepirdine content by LC-MS. The cognitive-enhancing nootropic effect was studied in male and female Wistar rats after 9 days of oral administration in corn oil at a dose of 10 mg/kg, after prior administration of scopolamine, an agent that causes memory impairment similar to that in Alzheimer’s disease. The animals’ cognitive function was studied in the passive avoidance test.Results: When studying the pharmacokinetics, the highest bioavailability both in the blood and in the brain was demonstrated by polymorph E, whose AUC was the highest relative to other polymorphs. In the study of the cognitive-enhancing nootropic effect, polymorph E also showed the highest activity, whose values of the latent period of entering the dark chamber did not differ from control animals, and differed from other polymorphs.Conclusion: Thus, the crystal structure has been shown to play a key role in the bioavailability and efficacy of latrepirdine, and polymorph E has also been shown to be a promising drug for the treatment of neurodegenerative diseases associated with memory impairment, such as Alzheimer’s disease.

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“…51 Studies have shown that patients with cognitive impairment exhibit low levels of NA C24:1 ω-9, and nutritional supplementation with NA C24:1 ω-9 is thought to enhance cognitive function and brain development. 37,52 Our previous study revealed that ASO supplementation can regulate FAs and improve cognitive function in healthy rats. We propose that the synergistic effect of NA with essential FAs induced by ASO supplementation contribute to the improvement of cognitive performance in HIE rats.…”

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties

“…33 The pharmacokinetics and cognitive-enhancing nootropic activity of the drug latrepirdine (Dimebon), that exists in 6 polymorphic forms, demonstrated that only one of the latrepirdine polymorphs showed significant nootropic activity, while five other patentprotected polymorphs did not provide any statistically significant therapeutic effect. 48 Difficulties in characterization and differentiation of five polymorphic forms resulted in the drug cefdinir, originally patented in both Japan and the US, 49−51 being simultaneously patent-protected by as many as 11 patents. 52 Unfortunately, the existence of polymorphs is impossible to predict based on a compound's structure.…”

“…For example, several clinical failures were reported for carbamazepine due to different polymorphs of the branded and generic drug, , and for which crystal engineering studies found as many as 13 new crystalline phases . The pharmacokinetics and cognitive-enhancing nootropic activity of the drug latrepirdine (Dimebon), that exists in 6 polymorphic forms, demonstrated that only one of the latrepirdine polymorphs showed significant nootropic activity, while five other patent-protected polymorphs did not provide any statistically significant therapeutic effect . Difficulties in characterization and differentiation of five polymorphic forms resulted in the drug cefdinir, originally patented in both Japan and the US, − being simultaneously patent-protected by as many as 11 patents …”