NMR spectroscopic determination of preferred conformations of quinidine and hydroquinidine.

NMR spectra of quinidine (I), hydroquinidine (II), and their respective acetyl derivatives (III and IV) were compared. The chemical shifts of some protons in I differed from those of their counterparts in II. These values were concentration dependent in I and II; they were similar in III and IV but not concentration dependent. The implications of these findings and the correlation of the NMR data with the preferred conformations are discussed.

Assignment of conformation and configuration to potassium permanganate oxidation products of quinidine.

Two epimeric aldehydes [(R)- and (S)-quinidinals] and the corresponding acids[(R)- and (S)-norhydroquinidinoic acids] were prepared by the oxidation of quinidine. The alpha-alpha interactions of the carbonyl group and the aromatic moiety, as reflected in the NMR spectra, were compared with those of quinidine. NMR spectroscopic analyses made it possible to assign both the stable conformation and their configuration at C-3 to these molecules. The free hydroxyl group at C-9 must be present for the chemical shift values to be concentration dependent. These findings provide more information on association in the parent molecules.

Impact of stable conformation of cinchona alkaloids on protonation site.

NMR analyses of quinidine and other cinchona alkaloids and their monoprotonated salts in deuterium oxide and in deuterochloroform revealed that the molecules assume new conformations in polar and nonpolar media, affecting the protonation site and hydrophilic-lipophilic characteristics. The ion-pair feature of the salts is lost and the molecules assume a neutral feature when they are transferred from an aqueous to a lipoid phase. Hydrophobic bonds between the molecules and their environment and within the molecule itself may affect the binding of cinchona alkaloids to membranes in biological fluids.

Relationship between quinidine concentrations measured in saliva and erythrocytes, and in serum.

The feasibility of indirect monitoring of serum quinidine concentration by determining saliva or erythrocyte levels was investigated in 16 hospitalized patients on quinidine therapy. No significant correlation was found between quinidine levels in saliva and its total or free levels in serum. The saliva to serum free drug concentration ratios were not dependent on saliva pH (r = 0.169), and they ranged from 1.238 to 6.782 among the different individuals. Quinidine serum protein binding was concentration dependent. It correlated poorly with serum levels of albumin, cholesterol, urea, creatinine, and patient's age. There was a significant positive correlation between quinidine concentration in erythrocytes (RBC) and its total or free concentration in serum (r = 0.481, p less than 0.05 and r = 0.770, p less than 0.001); however, the RBC to free serum concentration ratio varied appreciably among patients (range of ratio value 0.117 to 0.477) and did not significantly correlate with variables such as hematocrit or age. Thus, the estimation of serum protein binding of quinidine by determining its level in RBC is, as in the case of saliva, of limited usefulness. The means of the concentration of quinidine in blood, serum (total), RBC, and saliva in five patients after an overnight fast did not differ significantly from the means of the concentration determined after the consumption of lunch. Unbound quinidine levels in serum, on the other hand, were higher in the morning (1.31 micrograms/mg vs 1.01 micrograms/mg p less than 0.01). The administration of systemic heparin to one patient did not affect quinidine concentration in the various media in a consistent manner.