VARIABILITY IN THE PLASMA-PROTEIN BINDING OF VELNACRINE (1-HYDROXY TACRINE HYDROCHLORIDE) - A POTENTIAL AGENT FOR ALZHEIMERS-DISEASE

Objectives: To quantify the protein binding of velnacrine in healthy i ndividuals and investigate potential sources of variability. Setting: Medical School Unit, Southmead Hospital, Bristol. Subjects: Plasma sam ples 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 i llnesses. Methods: Aliquots of plasma from the above subjects were inc ubated with various concentrations of velnacrine, in the presence and absence of tacrine hydrochloride. Standard solutions of human serum al bumin and alpha(1) acid glycoprotein were incubated with velnacrine. T he degree of protein binding was determined using the Amicon centrifre e micropartition system. Results: 1) Over the range of concentrations from 10 to 320 ng . ml(-1), there was a decrease in protein binding fr om 59.1 to 46.7%. 2) At 40 ng . ml(-1) the plasma protein binding of v elnacrine was 54.8% in the group a subjects, 51.9% in the group b subj ects and 53.0% in the group c subjects (NS). 3) The mean total plasma protein concentration was significantly lower in the samples from elde rly subjects. The mean albumin and alpha(1) acid glycoprotein concentr ations were lower and higher respectively in patients with acute disea se. 4) Velnacrine was shown to bind to both albumin and alpha(1)-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 th e relationship between drug concentration and effect.