Posiphen and metabolites | Human plasma | Human CSF | Rat plasma | Rat brain | Rat CSF | |
Analyte | Parameters | (ng/ml) ± SD | (ng/ml) ± SD | (ng/ml) ± SD | (ng/g) ± SD | (ng/ml) ± SD |
Posiphen | Cmax | 118.5±24.8 | 1.6±0.6 | 144±69.5 | 979±429 | 9.5±4.6 |
*ClogP=2.22 | AUC0–last | 570±235.4 | ||||
N1-Norposiphen | Cmax | 25.6±6.7 | 1.7±0.7 | 56.3±8.7 | 213±27.9 | 2.8±1.1 |
ClogP=1.25 | AUC0–last | 214.4±77.1 | ||||
N8-Norposiphen | Cmax | 31±7.1 | 3.2±1.2 | 37.2±9.1 | 216± 28.6 | 2.8±5.8 |
ClogP=1.00 | AUC0–last | 261.3±91.3 | ||||
N1, N8-bisnorposiphen | Cmax | 3.8±1.2 | Not detected | 29.5±10.8 | 37.2±10.5 | Not detected |
ClogP=0.53 | AUC0–last | 36.9±12.5 |
Rat: A comparison is shown of plasma, brain and CSF levels of Posiphen and metabolites undertaken under steady-state conditions, which was achieved by continuous administration of Posiphen 75 mg/kg/day for 10 days by osmotic mini pump. In rat plasma (ng/ml) and brain (ng/g wet weight), Posiphen proved to be the primary drug compound, with the two major metabolites, N1- and N8-norposiphen, comprising up to 39.1% of Posiphen in plasma and up to 22% of Posiphen in brain at the Cmax. The third metabolite, N1, N8-bisnorposiphen, reached 20.4% of Posiphen in plasma and 3.8% of Posiphen at Cmax in brain. Human: the pharmacokinetic parameters of Posiphen and metabolites are shown in plasma and CSF of MCI patients after 10 days of 4×60 mg/day repeat dose oral administration, male and female subjects combined. As expected from the rodent data, the two primary metabolites N1- and N8-norposiphen constitute approximately 20% of Posiphen at the Cmax, with the third metabolite N1, N8-bisnorposiphen being a minor component and reaching only 3% of Posiphen Cmax. The time-dependent pharmacokinetic profiles of Posiphen and metabolites are provided in figure 3.
↵* The ClogP value is an established measure of a compound's lipid versus water solubility, with a positive value associated with a preference for the lipid phase.
MCI, mild cognitive impairment.