Plasma protein binding of tricyclic anti-depressants in man

Abstract The binding of various tricyclic antidepressants to human plasma and the effects thereupon of other drugs were studied by an ultrafiltration technique utilizing labeled compounds. At a total concentration of 0·29 μ/ml the percentage of unbound desmethylimipramine(DMI) was found to be 9·5 ± 1·4 in 41 individuals. The unbound fraction of DMI in plasma increased only twofold when the total concentration of the drug was increased a thousand times. The degree of binding over the entire range of therapeutic plasma drug concentration was relatively constant. The binding of various tricyclic antidepressants was compared at a drug concentration of 1·1 μM. The percentage of unbound drug was for nortriptyline (NT) 5·5 ± 0·6, for amitriptyline (AT) 3·6 ± 0·8, for imipramine (I) 4·2 ± 0·8, for protriptyline (PT) 8·0 ± 0·6 (tested at a cone, of 7·7 μM) and for Leo 640, an imipramine analogue, 0·7 ± 0·7. The acetyl derivatives of DMI, NT and PT were much more bound than the parent compounds. The addition of NT, PT or AT in a “therapeutic” concentration of 0·2 μg/ml didnot displace DMI, nor did chlorpromazine in supratherapeutic concentration. Diphenylhydantoin was found to displace DMI, NT, PT, AT and particularly I.