Variability in the plasma protein binding of velnacrine (1-hydroxy tacrine hydrochloride) A potential agent for Alzheimer’s disease

Abstract.

Objectives: To quantify the protein binding of velnacrine in healthy individuals and investigate potential sources of variability.

Setting:

Medical School Unit, Southmead Hospital, Bristol.

Subjects:

Plasma samples were obtained from the following groups:

a) 11 healthy volunteers aged 18 to 30 years;

b) 10 healthy volunteers aged 73 to 87 years;

c) 10 patients aged 65 to 85 years hospitalised for a variety of acute illnesses.

Methods:

Aliquots of plasma from the above subjects were incubated with various concentrations of velnacrine, in the presence and absence of tacrine hydrochloride. Standard solutions of human serum albumin and α₁ acid glycoprotein were incubated with velnacrine. The degree of protein binding was determined using the Amicon centrifree micropartition system.

Results:Over the range of concentrations from 10 to 320 ng ⋅ml⁻¹, there was a decrease in protein binding from 59.1 to 46.7%.

2) At 40 ng⋅ml⁻¹ the plasma protein binding of velnacrine was 54.8% in the group a subjects, 51.9% in the group b subjects and 53.0% in the group c subjects (NS).

3) The mean total plasma protein concentration was significantly lower in the samples from elderly subjects. The mean albumin and α₁ acid glycoprotein concentrations were lower and higher respectively in patients with acute disease.

4) Velnacrine was shown to bind to both albumin and α₁-acid glycoprotein, but together they did not account for total binding.

5) The binding of velnacrine was significantly decreased from 59.3 to 43.9% in the presence of a therapeutic concentration (25 ng ⋅ml⁻¹) of THA. There was no evidence that velnacrine displaced THA.

Conclusion:

Protein binding can be discounted as a major source of variation in the relationship between drug concentration and effect.