Variability in the plasma protein binding of velnacrine (1-hydroxy tacrine hydrochloride). A potential agent for Alzheimer's disease.
OBJECTIVE
To quantify the protein binding of velnacrine in healthy individuals and investigate potential sources of variability.


METHODS
Medical School Unit, Southmead Hospital, Bristol.


METHODS
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 alpha 1 acid glycoprotein were incubated with velnacrine. The degree of protein binding was determined using the Amicon centrifree micropartition system.


RESULTS
1) 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 alpha 1 acid glycoprotein concentrations were lower and higher respectively in patients with acute disease. 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.


CONCLUSIONS
Protein binding can be discounted as a major source of variation in the relationship between drug concentration and effect.
Wood
D M
DM
Department of Medicine, Bristol Royal Infirmary, UK.
Ford
J M
JM
Roberts
C J
CJ
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D001798:Blood Proteins; D002800:Cholinesterase Inhibitors; D009961:Orosomucoid; D012709:Serum Albumin; D013619:Tacrine; C056424:velnacrine