Odd G. Nilsen

Variable binding of propranolol in human serum.

Human serum proteins were fractionated by ultracentrifugation and gel filtration. Binding of propranolol was determined by equilibrium dialysis. Propranolol was distributed to lipoproteins independent of drug concentration. Two groups of propranolol binding sites were found to be present in the protein preparation containing albumin, α1-acid glycoprotein, transferrin and prealbumin. The first binding site with a dissociation constant of 7.5 × 10−7 was present in number equivalent to concentration of α1-acid glycoprotein. The propranolol binding to serum samples from 21 healthy males expressed as binding ratio B/F and per cent binding ranged from 7.5 to 19.2 and 88.2 to 95.0 respectively. The binding ratio was correlated to concentration of α1-acid glycoprotein (r = 0.85, P < 0.001), but not to concentrations of albumin and lipoproteins. The results indicate that α1-acid glycoprotein is the main propranolol binding protein in human serum.

Binding of quinidine in sera with different levels of triglycerides, cholesterol, and orosomucoid protein

Abstract Serum binding of quinidine was determined in vitro by equilibrium dialysis in sera from twenty-five healthy individuals. The sera had different levels of triglycerides, cholesterol and orosomucoid ( α 1 -acid glycoprotein), but with small variations in serum albumin concentration. Binding ratio (bound/free) and per cent binding varied from 2.0 to 5.4 and from 67.1 to 84.3% respectively. Binding ratios were linearly related to serum concentration of triglycerides ( r = 0.437, P r = 0.400 P r = 0.841, P r = 0.765, P r = 0.465, P r = 0.753, P

The binding of quinidine to protein fractions of normal human sera

Abstract In contrast to previous assumptions, albumin is not the only protein in normal human serum responsible for binding quinidine. Human serum proteins were fractionated by gel filtration and floatation. Quinidine binding was determined by equilibrium dialysis. The binding to low (LDL) and high (HDL) density lipoproteins exhibited two binding sites on each protein, and the dissociation constants K and number of binding sites n were calculated. LDL: K 1 = 2 × 10 −5 , n 1 = 1 and K 2 = 5·2 × 10 −4 , n 2 = 97. HDL: K 1 = 1·9 × 10 −5 , n 1 = 0·1 and K 2 = 1·1 × 10 −3 , n 2 = 14·7.

Effect of heparin and fatty acids on the binding of quinidine and warfarin in plasma

Abstract After an intravenous injection of heparin, the plasma protein binding of warfarin was greatly increased while the binding of quinidine seemed to be less affected. The increased binding of warfarin seemed partly due to the release of plasma non-esterified fatty acids, NEFA, but the level of NEFA alone could not explain the interindividual variations of plasma warfarin binding. Addition in vitro of palmitic acid to serum demonstrated an increased binding of warfarin and an unaltered binding of quinidine up to a serum NEFA level of 3.0 meq/l. Albumin isolated from post heparin plasma revealed an increased binding affinity for warfarin at the warfarin high affinity binding sites, and a slightly depressed affinity for quinidine. The low affinity binding sites on the albumin molecule for both drugs did not seem to be influenced by NEFA.

Neogene-Holocene rift propagation in central Tanzania: Morphostructural and aeromagnetic evidence from the Kilombero area

Based on field studies supplemented by remote sensing and aeromagnetic data from central Tanzania, a Phanerozoic structural history for the region can be developed and placed in a broader rift context. The major contribution of this work is the recognition of rift morphology over an area lying 400 km beyond the southern termination of the Eastern, or Kenya, Rift. The most prominent rift structures occur in the Kilombero region and consist of a wide range of uplifted basement blocks fringed to the west by an east-facing half-graben that may contain 6–8 km of sedimentary strata. Physiographic features and river drainage anomalies suggest that Holocene/Neogene deformation occurs along both rift-parallel and transverse faults, in agreement with the seismogenic character of a number of oblique faults. The present-day rift pattern of the Kilombero extensional province results from the complete overprinting of an earlier (Karoo) rift basin by Neogene- Holocene faults. The Kilombero rift zone is assumed to connect northward into the central rift arm (Manyara) of the Eastern Rift via an active transverse fault zone. The proposed rift model implies that incipient rifting propagates throughout the cold and strong lithosphere of central Tanzania following Proterozoic basement weakness zones (N140°E) and earlier Karoo rift structures (north-south). An eventual structural connection of the Kilombero rift zone with the Lake Malawi rift further south is also envisaged and should imply the spatial link of the eastern and western branches of the East African Rift System south of the Tanzanian craton.

Serum albumin and lipoproteins as the quinidine binding molecules in normal human sera

Abstract To substantiate the binding of quinidine in human sera and predict variations of binding dissociation constants and number of binding sites were determined for separate serum proteins. Human sera were fractionated by gel filtration and ultracentrifugation, and binding was evaluated by equilibrium dialysis at pH 7·30 at 20° and 37° in a Krebs-Ringer phosphate buffer. Quinidine was bound to all serum lipoproteins and to serum albumin. The binding was influenced by the buffer composition. In sodium phosphate buffer there were two separate binding sites for quinidine on LDL and HDL, while there was only one detectable binding site on VLDL and HDL in a Krebs-Ringer phosphate buffer. On LDL also there appeared to be one binding site but it exhibited a positive cooperative binding effect at lower concentrations of quinidine. This effect was assumed to be caused by inorganic ions of the Krebs-Ringer phosphate buffer. At a therapeutic level of quinidine in normal human serum the concentration of quinidine bound to serum proteins was 1·062 × 10−5 M. Calculated from the evaluated binding parameters VLDL contributed with 0·101 × 10−5 M of this binding, LDL with 0·143 × 10−5 M, HDL with 0·083 × 10−5 M and albumin with 0·699 × 10−5 M.

Pharmacokinetics of quinidine related to plasma protein binding in man.

SummaryThe disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p<0.01) and total body clearance (r=0.668, p<0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.

Increased binding of quinidine to serum albumin and lipoproteins in anuric rats

The purpose of this work was to identify the main quinidine binding molecules of rat serum and those macromolecules responsible for increased quinidine binding in serum from rats with acute anuria. Rat sera were fractionated by gel filtration, ultracentrifugation and anion exchange chromatography. The binding of quinidine to sera and serum fractions was determined by equilibrium dialysis. The experiments demonstrated that albumin and lipoproteins are the main quinidine binding molecules in serum from normal and anuric rats. The increased binding by serum from anuric rats is due to both serum lipoproteins and albumin, even though the concentration of albumin is decreased from 2.8 to 1.7 g/100 ml. The increased binding to albumin may be due to conformation changes induced by endogenous substances. The increased binding to lipoproteins may be caused by an increased concentration of pre-beta-lipoprotein.

The influence of salts and differences in protein isolation procedure on the binding of quinidine to human serum albumin

Abstract The influence of buffer and two different albumin preparations on the albumin-quinidine interaction was investigated. Human serum albumin was prepared by either alcohol fractionation or ultracentrifugation with subsequent gel filtration. The interaction between albumin and quinidine was determined by equilibrium dialysis. It was inhibited by halide ions and consequently different binding parameters were found to be valid for the complex in sodium phosphate and in Krebs-Ringer phosphate buffer. The influence of Ca 2+ , Mg 2+ and SO 2− 4 in physiological amounts was negligible. The albumin obtained by alcohol fractionation possessed one binding site for quinidine, while the albumin isolated by ultracentrifugation with subsequent gel filtration possessed two binding sites when tested in a Krebs-Ringer phosphate buffer. In sodium phosphate buffer both albumin preparations had two independent binding sites, and showed essentially identical binding parameters.

Absorption of quinidine from an enteric-coated preparation.

SummaryThe absorption of quinidine from single and multiple doses of an enteric-coated preparation (Systodin®) was studied in seven healthy subjects, and was compared with the pharmacokinetics of intravenously administered quinidine and the results of in vitro dissolution tests of the tablets. Absorption of quinidine began after a variable delay, 2–8 h (mean 4.8) after fasting and 3–10 h (mean 6.1) after food. The rate of absorption varied both in and between individuals. It appeared to be lower when the drug was administered after food. Multiple doses after food gave a pattern of plasma concentration-time curves similar to that found on administration of single doses after food. The delay prior to absorption was prolonged at night. The ratio between the maximum and minimum concentration of quinidine during a dose interval varied from 1.3 to 3.2 (mean 2.0). Bioavailability of quinidine in fasting subjects ranged from 69 to 95% (mean 83); variation was greater when doses were administered after food. The release of quinidine from the enteric-coated preparation was pH dependent and was sustained at low pHs as may be found in the intestines. The results indicate that the absorption of quinidine from the enteric-coated formulation was dependent on the highly variable rate of gastric emptying and the pH of intestinal fluid, and it varied greatly both within and between individuals.