Significance of lipoproteins in serum binding variations of amitriptyline, nortriptyline, and quinidine

Abstract

Using isotope technique, the serum binding of amitriptyline (AT), nortriptyline (NT), and quinidine (Q) was measured by equilibrium dialysis in sera containing varying amounts of lipoproteins. Sera were obtained from 10 fasting subjects with normal to grossly elevated levels of cholesterol, triglycerides, or both. When the lipoproteins were removed from eight of the sera by a standard ultracentrifugation technique, the ratio bound/unbound (B/F) AT decreased an average of 47% (range 30% to 68%), NT an average of 54% (range 39% to 67%), and Q an average of 6% (range 0 to 16%). This decrease in the ratio B/F correlated linearly with the sum of serum concentrations of cholesterol and triglycerides for AT (r = 0.88) and NT (r = 0.82), but not for Q (r = 0.15). In three lipoprotein-depleted sera resuspended with lipoproteins at eight different concentrations ranging from 0 to 100% of the original content, there was a linear correlation between the ratio B/F for AT and NT and the lipoproteins, as evidence by cholesterol or triglycerides concentrations (r = 0.97 to 0.99), but not for Q (r = -0.17 to 0.36). Finally, in the original 10 serum samples, there was a linear correlation between the ratio B/F and the serum lipoproteins (sum of cholesterol and triglycerides) for AT (r = 0.89) and NT (r = 0.68), whereas there was no such relationship for Q (r = -0.15). These data indicate that basic drugs differ in binding characteristics (probably depending on lipophility).

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

“…An explanation involving two different binding sites on AAG is unlikely since only one common binding site to AAG for basic drugs has been identified so far (Muller & Stillbauer, 1983;Goolkasian et al, 1983). Much of the literature on the relative contribution of a protein to overall binding is derived from experiments using purified proteins, but such results may not reflect the situation in whole serum adequately (Pike et al, 1982(Pike et al, , 1984. Certainly, the binding of drugs to AAG can be increased in the presence of albumin (Owens et al, 1983).…”

“…In principle both components of the MM could be responsible for the interaction. Lecithin binds to lipoproteins (Jonas, 1979;Scherphof & Morselt, 1984) as do several drugs and vitamins (Hobbelen et al, 1975;Takahashi et al, 1977;Lemaire & Tillement, 1982), in particular those with basic properties (Bickel, 1975;Chen & Danon, 1979;Pike et al, 1982).…”

Drug binding in sera deficient in lipoproteins, albumin or orosomucoid.

“…This was shown also by Brinkschulte & Breyer-Pfaff (1980). In a previous study (Pike et al, 1982b) we demonstrated a high degree of correlation Piafsky, 1980). Thus, Nilsen & Jacobsen (1975) showed that quinidine bound to isolated lipoproteins and Sager et al (1979) (Sager etal., 1981) may indicate some role of the lipoproteins as well.…”

“…Serum was stored in glass tubes at -20°C until analysed (within 1 month and re-tested 9 months later). Previous studies (Pike & Skuterud, 1983) (Pike et al, 1982b).…”

“…Stability of isolated lipoproteins Since preparation of albumin deficient serum depends on removal and subsequent restoring of the serum lipoproteins, the binding stability of these isolated lipoproteins was examined for drugs whose binding in total serum is also determined by the lipoprotein content (Pike et al, 1982b The reproducibility ofmethods Serving as a control for the lipoprotein deficient serum, the albumin de-ficient serum and the regenerated normal serum, the KBr control serum was examined by drug binding properties after 0, 2 and 8 days storage at 40 C. In addition the KBr serum was re-examined after storing for 9 months at -20°C. The following mean values (± I s.d.)…”