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Some Quantitative Aspects of the Binding of Quinidine and Related Quinoline Compounds by Human Serum Albumin

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Some Quantitative Aspects of the Binding of Quinidine and Related Quinoline Compounds by Human Serum Albumin SOME QUANTITATIVE ASPECTS OF THE BINDING OF QUINIDINE AND RELATED QUINOLINE COMPOUNDS BY HUMAN SERUM ALBUMIN Hadley L. Conn Jr., Robert J. Luchi J Clin Invest. 1961;40(3):509-516. https://doi.org/10.1172/JCI104278. Research Article Find the latest version: https://jci.me/104278/pdf SOME QUANTITATIVE ASPECTS OF THE BINDING OF QUINIDINE AND RELATED QUINOLINE COMPOUNDS BY HUMAN SERUM ALBUMIN * By HADLEY L. CONN, JR. AND ROBERT J. LUCHI t (From the Robinette Foundation, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa.) (Submitted for publication August 18, 1960; accepted November 21, 1960) The interaction of quinidine with various body butions to binding by the various reactive sites or proteins may well be the fundamental process areas in the quinidine molecule. through which quinidine exerts its many effects. For example, quinidine binding with membrane METHODS lipoprotein may lead to decreased membrane per- A dialysis equilibrium technique was used to evaluate meability to passive ion movement. This perme- the in vitro binding of quinidine and of similar chemicals ability change has been held responsible for the to human serum albumin.' A limited investigation of quinidine binding to human y-globulin was carried out quinidine-induced alterations in sodium and po- in the same manner.2 A cellulose dialysis membrane3 tassium exchange in cardiac muscle (1-4). Quin- was prepared by an initial wash with 1 per cent sodium idine binding with critical enzyme proteins may carbonate and a subsequent wash with distilled water. be responsible for the alterations in intermediary Twenty ml of 0.2 M phosphate buffer solution contain- metabolism which have been ascribed to quinidine ing 250 mg of human serum albumin was placed in a dialysis bag. Fifty ml of the same buffer solution was (5). In our experience, glucose-6-phosphate de- placed around the bag in a plastic beaker. To this, ex- hydrogenase activity is reduced in vitro by quini- ternal solution quinidine and other substances were added dine. Finally, the known binding of quinidine to as desired. The beaker was then covered tightly with albumin may protect the cell against the action of Saran wrap and shaken mechanically at 25° C until quinidine by making less drug available at cellu- equilibrium had been achieved. In practice this was lar sites. The nature of the interaction with pro- found to occur within 18 hours. Quinidine may be considered structurally as 4-hydroxy- tein of quinidine and of other compounds having a methyl-6-methoxy-quinoline connected by the secondary similar chemical structure seemed, therefore, to alcohol bridge to a quinuclidine ring. Therefore, not warrant an investigation. only was the effect of quinidine binding to albumin stud- Albumin is readily available in adequate amounts ied but also the binding to albumin of 4-hydroxymethyl- 6-methoxy-quinoline,4 6-methoxy-quinoline, 4-hydroxy- and in relative purity. As noted above, it is methyl quinoline,5 quinoline, and naphthalene. The hy- known to complex with quinidine. Further, the drochloride salt was used in all cases except that of state of the quinidine-albumin interaction might naphthalene. These compounds were used as a means be considered as a prototype of the "protective" of evaluating the contribution of binding of the various form and perhaps characteristic of all forms of parts of the quinoline molecule. In addition, the com- petitive or inhibitory effects of all of the above sub- quinidine binding to protein. For these reasons stances, except naphthalene, on quinidine-albumin bind- our initial investigations were concerned with the ing were studied during the presence both of quinidine reactions of quinidine and related quinoline com- and of one of the other compounds in the system. The pounds with albumin. Experiments were de- part played in the binding reaction by the quinuclidine signed to permit determination of the stoichiom- 1 Obtained from the Red Cross in solution form and etry, the association constant, and the energies of from Pentex Co., Kankakee, Ill., in crystalline form. binding for the reactions; and to show the contri- On paper electrophoresis both migrated as homogeneous peaks corresponding to albumin when barbital buffer * This study was supported by grants from the Atomic (pH 8.6) and an ionic strength of 0.075 were used. Energy Commission and the American Heart Associa- 2 Obtained from Sharp and Dohme, division of Merck, tion. Inc., Philadelphia, Pa. t Supported in part by United States Public Health 3A. H. Thomas Company, Philadelphia, Pa. Service Grant H5663 and a grant from the Pharmaceuti- 4 5 Synthesized with the generous aid of R. W. Greeff cal Manufacturers Association. and Co., Nederlandsche Kininefabriek, Maarsen, Holland. 509 510 HADLEY L. CONN, JR. AND ROBERT J. LUCHI TABLE I Binding of quinidine and related compounds to albumin B* Cqt Cat B Cq Ca Quinidine 6-Methoxy-quinoline 62 ± 3 3.0 X 10-6 2 X 10-4 n§ = 1.0 67 5 6.0 X 10-6 2 X 10-4 n = 6.1 60 3 6.0 X 10-6 2 X 10-4 66 2 1.2 X 10-5 2 X 10-4 55 2 3.2 X 10-5 2 X 10-4 46 2 8.0 X 10-4 2 X 10-4 Kd = 6.0 X 10-4 34 ± 4 2.0 X 10-4 2 X 10-4 Kdl= 1.3 X 10-4 36 ± 2 1.6 X 10-3 2 X 10-4 K, = 1.7 X 103 28±1 4.0X10-4 2X10-4 19 3 8.1 X 10-4 2 X 10-4 4-Hydroxymethyl-quinoline 9 2 2.2 X 10-3 2 X 10-4 KaT = 7.7 X 103 42 ± 4 8.0 X 10-6 2 X 10-4 n = 3.9 9.0 4-Hydroxymethyl-6-methoxy-quinoline 2818±==2± 2 2.4 XX10-310-4 2 X10-4X 10-4 Kd =9.0 X10-4 73 ± 4 5.5 X 10-6 2 X 10-4 n = 2.9 12 ± 2 4.5 X 10-3 2 X 10-4 Ka = 1.1 X 103 72 ± 4 1.0 X 10-5 2 X 10-4 50 ±-~ 2 3.6 X 10-4 2 X 10-4 Kd = 2.0 X 10-Qio4n 38 ± 3 7.0 X 10-4 2 X 10-4 Quinoline 25 ± 3 1.4 X 10-3 2 X 10-4 Ka = 5.0 X 103 50 ± 2 8.0 X 10-6 2 X 10-4 n = 8.1 48 i 1 1.6 ± 10-5 2 X 10-4 Naphthalene 40 1 3 8.0 X 10-4 2 X 10-4 Kd = 1.7 X 10-3 66 2 1.3 X 10-4 2 X 10-4 n = 67.0 34 ±t 3 1.3 X 10-3 2 X 10-4 65 2 2.5 X 10-4 2 X 10-4 Kd = 6.6 X 10-3 19 ± 2 5.4 X 10-3 2 X 10-4 Ka = 6.0 X 102 Ka = 1.5 X 102 * Per cent bound, with standard deviation. t Free molar concentration of drug. t Molar concentration of albumin. § Number of areas available for drug binding per mole of albumin. Dissociation constant of drug-albumin complex. ¶ Association constant of drug-albumin complex. ring was evaluated in part through a study of the in- calculated after a minor correction for the Donnan effect hibitory effects of triethylene diamine (TED) and of of protein. benzyl alcohol on the quinidine-albumin interaction. The stoichiometric relationships and the dissociation Quinidine concentration in protein and nonprotein sol- constants of the drug-albumin complexes were evaluated utions was determined in the Beckman DU spectropho- as follows. The determinations of the bound fraction tometer by the method of Josephson, Udenfriend and of the drug were made after the addition to the system Brodie with ethylene dichloride as the extracting agent of amounts of quinidine and/or quinoline compound (6). The concentrations of 4-hydroxymethyl-6-methoxy- varying from 100 to 50,000 yg. The formula reproduced quinoline, 6-methoxy-quinoline, 4-hydroxymethyl-quino- by Goldstein (7) was solved to obtain values for the un- line, quinoline, and naphthalene were determined in a knowns, K and n, which represent the dissociation con- similar fashion. However, the concentration of the first stant and the stoichiometric relationships, respectively. two compounds, as well as that of quinidine, was deter- mined at 250 miu, while that of the 4-hydroxymethyl- The formula is 0 = 1 + (K/nP) + (x/nP)where quinoline and quinoline was determined at 235 mju and equals the fraction of bound to total drug, K equals the that of naphthalene at 220 myA. In those experiments in dissociation constant of the drug-protein complex, x which use was made of two compounds, both having an equals the molar concentration of free drug, n equals the appreciable reading at the same wave length, the com- number of receptor locations in the albumin molecule for pounds were first separated on an acid alumina (Woelm) each drug molecule, and P is the molar concentration of column with a solvent phase consisting of increasing the protein, here albumin. From the experimental data, (0.5 and 4.0 per cent) concentrations of ethanol in solutions for the two unknowns were achieved either ethylene dichloride. Simultaneous recovery experiments through the use of simultaneous equations or through the were carried out following the addition of measured graphic plotting described by Goldstein (7). The asso- amounts of these various compounds both to the albu- ciation constant was derived as the reciprocal of the min and to the buffer solution of the dialysis system.
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