Enantiomer protein binding

Phenylbutazone was recognised to potentiate the anticoagulant effect of warfarin as long ago as 1959. As subsequent in vitro studies confirmed that phenylbutazone displaced warfarin from its protein binding site, it was assumed that any non-steroidal antiinflammatory drug (NSAID) would enhance warfarin s anticoagulant effect in this way. However it is now known that the interaction is due instead to a stereoselective inhibition of the metabolism of warfarin. Warfarin is available as a racemic mixture of two enantiomers R and S), and of these the S enantiomer is five times more potent as an anticoagulant. Phenylbutazone inhibits the metabolism of the... 

The racemic compound bupivacaine, which was first synthesized by Ekenstam et al. in 1957, is an amide-type LA with a high lipophilicity, protein binding and pKa giving rise to an intermediate onset and a long duration of action. At the same time, bupivacaine has a high toxicity potential relatively often associated with convulsions and life-threatening cardivascular collapse (Moore et al., 1978). Levobupivacaine, the (S)-enantiomer of bupivacaine, has recently been developed for clinical use addressing the enantioselectivity of side-effects of bupivacaine (see below). 

Etodolac is highly protein bound (greater than 95%) [38]. At low concentrations, the (R)-etodolac enantiomer shows higher protein binding than does the (S)-etodolac enantiomer. Interestingly, the opposite is true at higher concentrations [43]. 

The PPB of racemic drugs is potentially stereoselective, as a consequence of chiral discriminative properties of the binding sites of the protein fractions. However, the limited available data on the binding of enantiomers indicate the differences are small (Pacifici and Viani 1992). The concentrations of total protein, albumin and a-acid glycoprotein in plasma differs slightly between human and animal species (Davies and Morris 1993). Interspecies differences in the stereoselectivity of protein binding have been reported for various drags (Lima 1988 Lin et al. 1990,1991). 

Jin, Y.X., Tang, Y.H., Zeng, S. Analysis of flurbiprofen, ketoprofen and etodolac enantiomers by pre-column derivatization RP-HPLC and application to drug-protein binding in human plasma. J. Pharm. Biomed. Anal. 46, 953-958 (2008)... 

Protein type CSPs have to be considered as important and widely used tools for enantiomer separations (Table 9.9) and for analyzing stereoselective phenomena of biological significance, in particular for stereoselective drug-protein binding studies. The latter application, however, is beyond the scope of this report and the reader is referred to recent articles on this topic [4,223-232]. 

A. S. Gross, B, Heuer, and M. Eichelbaum, Stereoselective protein binding of verapamil enantiomers, Biochem. Pharmac<., 37 4623-4627 (1988). 

The binding of the chiral BDZ oxazepam hemisuccinate (OXH see Fig. 2) to HSA is a particularly striking example of enantioselective protein binding (29). As indicated in Table 2, the ratios of the affinity constants of the two enantiomers when binding to HSA may be as high as 50, depend-... 

The concentration of AGP in the plasma of healthy volunteers correlated significantly with the binding ratio (bound/free) of the enantiomers, as well as the racemic form, of methadone. The average free fractions for +)- and (—)-methadone in plasma were 0.100 and 0.142, respectively (97). Two variants of AGP, orosomucoids 2A and FI, were also found to play important determining roles in the binding of methadone enantiomers (97). The authors of the study point out that the levels of AGP variants should be considered in protein binding studies. 

Rabbits that had been rendered uremic, by administration of uranyl nitrate, displayed an enantioselective decrease in the plasma protein binding of 2-phenylpropionic acid, the effect being more pronounced for the highly bound R-enantiomer (123). This behavior was repeated in a small group of uremic patients admmistered racemic flurbiprofen. The enantiomeric ratio of free (R) (S) flurbiprofen increased from 1.1 in healthy individuals to 1.4 in the uremic group (55). 

A. Yacobi and G. Levy, Protein binding of warfarin enantiomers in serum of humans and rats, /. Pharmacokinet. Biojdtarm., 5 123 (1977). 

D. Ofori-Adjei, B. Ericsson, B. Linstrbm, and E Sjdquist, Protein binding of chloroquine enantiomers and desethylchloroquine, Br. /. Ciin. Pharmacol., 22 356 (1986). 

H. Takahashi, H. Ogata, S. Kanno, and H. Takeuchi, Plasma protein binding of propranolol enantiomers as a major determinant of their stereoselective tissue distribution in rats, J. Pharmacd. Exp. Then, 252 272 (1990). 

K. M. McErlane, L. Igwemezie, and C. R. Kerr, Stereoselective serum protein binding of mexiletine enantiomers in man. Res. Commun. Chem. Pathy. Pharmacy., 56 141 (1987). 

S. B. Earle and J. J. Mackichan, Separation and protein binding of verapamil enantiomers, Cfin. Pharmacol. Ther., 41 233 (1987). 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

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