Nose-to-brain delivery of tacrine

Abstract

In the treatment of Alzheimer's disease tacrine, a cholinesterase inhibitor, is not the drug of choice due to its low oral bioavailability, extensive hepatic first-pass effect, rapid clearance from the systemic circulation, pronounced hepatotoxicity, and the availability of drugs better than tacrine in the same pharmacological class. Hence, the aim of this investigation was to ascertain the possibility of direct nose-to-brain delivery of tacrine to improve bioavailability, to avoid the first-pass effect and to minimize hepatotoxicity. Tacrine solution (TS) in propylene glycol was radiolabelled with (99m)Tc (technetium) and administered in BALB/c mice intranasally (i.n.) and intravenously (i.v.). Drug concentrations in blood and brain were determined at predetermined time intervals post dosing. Drug targeting efficiency (DTE %) and the brain drug direct transport percentage (DTP %) were calculated to evaluate the brain targeting efficiency. Brain scintigraphy imaging in rabbits was performed to ascertain the uptake of the drug into the brain. Tacrine solution was effectively labelled with (99m)Tc and was found to be stable and suitable for in-vivo studies. Following intranasal administration tacrine was delivered quickly (T(max) 60 min) to the brain compared with intravenous administration (T(max) 120 min). The brain/blood ratios of the drug were found to be higher for [(99m)Tc]TS(i.n.) compared with [(99m)Tc]TS(i.v.) at all time points. The DTE (207.23%) and DTP (51.75%) following intranasal administration suggested that part of tacrine was directly transported to brain from the nasal cavity. Rabbit brain scintigraphy imaging showed higher uptake of the drug into the brain following intranasal administration compared with intravenous administration. The results showed that tacrine could be directly transported into the brain from the nasal cavity and intranasal administration resulted in higher bioavailability of drug with reduced distribution into non-targeted tissues. This selective localization of tacrine in the brain may be helpful in reducing dose, frequency of dosing and dose-dependent side effects, and may prove an interesting new approach in delivery of the drug to the brain for the treatment of Alzheimer's disease.

Validation of Anatomical Models to Study Aerosol Deposition in Human Nasal Cavities

“…Potential use of the nasal route to deliver medications to the brain has been widely investigated, in particular for morphine and also several peptides and proteins (6–8) or Tacrine®, a cholinesterase inhibitor currently being developed to treat Alzheimer's disease, which has a very low oral bioavailability (9,10). …”

Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: Effects on food-reinforced behavior and comparisons with AM4113

“…One of the important criteria for establishing whether or not a drug may be useful clinically is the determination of the oral bioavailability of that drug (Jogani et al, 2007; Ohta et al, 2007). Several previous studies have shown that rimonabant is orally active (Huestis et al, 2001; Costa et al, 2005; Davis and Nomikos, 2008).…”

Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061

“…For example, morphine for cancer pain, lidocaine for migraine, tacrine for Alzheimer's disease and scopolamine for motion sickness (Costantino et al 2007). There are different reasons for choosing intranasal as the dose route of interest, for example, to improve exposure relative to oral administration (apomorphine), to decrease the time to onset of effect by reducing T max , for example, zolmitriptan for migraine (Costantino et al 2007) and also, and maybe more controversial, to provide a direct route via the olfactory epithelium to the brain avoiding the blood-brain barrier and systemic circulation altogether, for example, tacrine, a treatment for Alzheimer's disease (Jogani et al 2007).…”