Evaluation of enantioselective binding of basic drugs to plasma by ACE

Abstract

The present paper deals with the evaluation of the stereoselective binding of antihistamines (brompheniramine, chlorpheniramine, hydroxyzine, orphenadrine and phenindamine), phenothiazines (promethazine and trimeprazine) and a local anesthetic (bupivacaine) to human plasma proteins. Since all of them are drugs highly bound to proteins, a methodology to determine the bound fraction of each drug enantiomer was proposed. This methodology includes the incubation of samples containing plasma and racemic drug, ultrafiltration of the mixture and the chiral separation of enantiomers in the bound drug fraction using affinity EKC (AEKC)-partial filling technique and HSA as chiral selector. The results shown in this paper represent the first evidence of the enantioselective binding of some antihistamines such as brompheniramine, hydroxyzine, orphenadrine and phenindamine and the phenothiazines, promethazine and trimeprazine, to human plasma proteins. The binding of phenindamine to plasma presented the highest enantioselectivity (ES) (ES = 2.5) followed by trimeprazine (ES = 1.5) and promethazine (ES = 1.4).

Microseparation techniques for the study of the enantioselectivity of drug–plasma protein binding

“…Ultrafiltration combined with chiral separation techniques (Table 1) has been used in the literature for evaluating the stereoselectivity in binding of bimoclomol to HSA, AGP and plasma ; alprenolol to AGP (Imamura et al, 2002) or the tryptophan to bovine serum albumin (BSA) (Randon et al, 2000); warfarin, phenprocoumon and acenocoumarol have been tested for their stereoselective binding to AGP (Hazai et al, 2006); mefloquine to HSA and AGP (Zsila et al, 2008); individual sulbenicillin enantiomers to HSA (Tsuda et al, 2001); ketoprofen to HSA (Lagrange et al, 2000); aminohydantoins in rat, dog and human plasma (Peng et al, 1999); dihydrodiazepam and lorazepam acetate to AGP (Fitos et al, 1995); carbenicillin to HSA (Itoh et al, 1996); antihistamines to HSA; and basic drugs to plasma (Martínez-Gómez et al, 2007a;2007b).…”

“…Levels of the free (+)-(S)-enantiomer were higher than its (−)-(R)-antipode at steady state in patients with obliterative atherosclerosis (Glówka and Caldwell, 2002). Martínez-Gómez et al (2007b) studied the enantioselective binding of five antihistamines (brompheniramine, chlorpheniramine, hydroxyzine, orphenadrine and phenindamine), two phenothiazines (promethazine and trimeprazine) and a local anaesthetic (bupivacaine) to whole plasma by determining the protein binding of drug enantiomers. Owing to the high protein binding values of these drugs the authors used the methodology previously described (Martínez-Gómez et al, 2007a).…”

Affinity capillary electrophoresis and fluorescence spectroscopy for studying enantioselective interactions between omeprazole enantiomer and human serum albumin

“…Human serum albumin, which accounts for 60% of the total plasma protein, is the most important and abundant protein in the circulatory system. It is often used as a chiral selector to investigate the interaction between drugs and model protein since HSA inherently possessed chiral selectivity . Because HSA can provide specific recognition sites for biding a variety of pharmaceutical and biological chiral analytes, it exhibit high potential stereoselectivity towards many chiral drugs.…”

Combination of poly(diallyldimethylammonium chloride) and hydroxypropyl-γ-cyclodextrin for high-speed enantioseparation of phenothiazines by capillary electrophoresis

“…Compared with HPLC, CE is highly appealing because of the small sample injection volumes required, low solvent consumption, short analysis time [11], and high separation efficiency [12,13]. Adding a chiral selector, such as macrocyclic antibiotics [14], proteins [15,16], or cyclodextrin (CD) derivatives [17,18], to the background electrolyte results in efficient separation of D,L-phenothiazines. For example, DL-Tri and DL-Pro were completely enantioseparated by partially filling a capillary with human serum albumin [13].…”