Enantiomer terbutaline

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol. 

Recently, the separation of some milligram quantities of terbutaline by classical gel electrophoresis has been reported [194]. A sulfated cyclodextrin impregnated on the agarose gel was used as a chiral selector and the complete resolution was achieved in 5 h. Analogously, small amounts of enantiomers can be isolated using thin-layer... 

Kim, K.H., Kim, H.J., Kim, J.-H., Shin, S.D. (2001). Determination of terbutaline enantiomers in human urine by coupled achiral-chiral performance liquid chromatography with fluorescence detection. Chromatogr. B 751, 69-77. 

Walhagen, A., Edholm, L.E., Kennedy, B.M., Xiao, L.C. (1989a). Determination of terbutaline enantiomers in biological samples using liquid chromatography with coupled columns. Chirality 1, 20-26. 

Online-dual-column extraction coupled to enantioselective LC-MS was used for the determination of terbutaline enantiomers in human plasma on a commercially available TE CSP [120]. 

Xia, Y.-Q., Liu, D.Q., and Bakhtiar, R., Use of online-dual-column extraction in conjunction with chiral liquid chromatography tandem mass spectrometry for determination of terbutaline enantiomers in human plasma. Chirality, 14, 742, 2002. 

Determination of drug enantiomers in biological samples by coupled column liquid chromatography and liquid chromatography-mass spectrometry" (72). The direct separation and determination of the enantiomeric composition of terbutaline in human plasma at the nmol/L level... 

TSP LC-MS in combination with coupled-column chromatography was used to separate and determine drag enantiomers of terbutaline (225 Da) in human plasma [76]. The (-)terbutaline enantiomer is pharmacologically active. The method was developed for single-dose pharmacokinetic studies to determine the plasma... 

Figure 4.13 Coupled-column LC-MS system for the determination of terbutaline enantiomers in plasma (Reprinted with permission from [76], 1988, Elsevier Science).

The SULT 1 A3 displays stereoselectivity in the sulfation of chiral phenolic phenethanolamines. This isotorm may be responsible, in part, for the enantiomer-specific metabolism observed for the p-adrenergic agonists. For example, the (-rj-enantiomers of terbutaline and isoproterenol and the (-)-enantiomer of albuterol are selectively sulfated. 

Kim, K.H. Park, Y.H. Enantioselective inclusion between terbutaline enantiomers and hydroxypropyl-P-cyclodextrin. Int. J. Pharm. 1998, 175 (1),... 

Stereoselectivity in the pharmacodynamics of p2-agonists has been extensively studied at both the receptor and the end-clinical response levels [82-95]. Except for trimethoquinol, the bronchodilator action of all p2-agonists is predominantly due to the R enantiomer. Using excised tissues from various animals and humans, it has been shown that p2-adrenoceptor agonist activity resides mainly with the R or (R,R) isomers of racemic albuterol, terbutaline, formoterol, and clenbuterol (Table 5) [82-95]. 

The major pharmacokinetic parameters of albuterol and terbutaline are listed in Tables 1 and 2. Irrespective of the route of administration, the pharmacokinetics of racemic albuterol are stereoselective with a faster disappearance of the active R enantiomer from plasma (Tables 1 and 2). This is due to stereoselective metabolism and renal clearance of albuterol in favor of the R enantiomer. Both the total body and renal clearances of R-albuterol are approximately 2 to 3 times higher than those of the distomer, resulting in a >3-fold higher maximum plasma concentrations of... 

Enantioselectivity in the renal clearance of chiral p2-agonists has been reported for albuterol and terbutaline [112,114,117], After the IV administration of albuterol enantiomers and racemic albuterol, the renal clearance of the individual enantiomers and racemic drug exceeded creatinine clearance, thus implicating active tubular secretion in the urinary elimination of the drug. Renal clearance of R-albuterol was reported to be two- or threefold higher than that of S-albuterol [114]. Since plasma protein binding of albuterol is low [112], the differences in the renal clearance of albuterol enantiomers may be attributed to stereoselectivity in active tubular secretion. 

As with albuterol, terbutaline renal clearance also exceeds creatinine clearance, indicating the involvement of active tubular secretion in the renal excretion of the drug. However, the direction of stereoselectivity in the renal clearance of terbutaline is opposite to that of albuterol. After IV doses of racemic terbutaline or the individual enantiomers, renal clearance of the S-enantiomer is approximately twice that of its antipode [117]. 

In contrast to albuterol, plasma concentrations of R-terbutaline are significantly higher than those of its inactive S enantiomer (Table 1). Borgstrom et al. [117] investigated the plasma pharmacokinetics of terbutaline enantiomers after single IV and oral doses of single enantiomers or the racemate. The IV doses were 0.125 mg of S or R enantiomer or 0.5 mg of the racemate, and oral doses were 5 mg of R- or S-terbutaline or the racemate. Mean steady-state volumes of distribution of enantiomers were similar (1.9L/kg), although mean clearance was 0.19 and 0.13L/h/kg for... 

S-terbutaline and R-terbutaline, respectively. The differences in clearance of enantiomers were primarily due to stereoselectivity in renal clearance. However, the nonrenal clearances of enantiomers were similar, suggesting a lack of stereoselectivity in the formation of sulfate conjugates in the liver. Indeed, urinary recoveries of conjugates after IV administration were similar for both enantiomers. After oral doses, the plasma concentrations of the R-enantiomer were approximately twice those of S-terbutaline. Intestinal metabolism in favor of the S enantiomer was considered to be the primary cause of stereoselectivity in terbutaline pharmacokinetics and bioavailability after its oral administration [117]. 

Jeppsson, A.B. Johansson, U. Waldeck, B. Steric aspects of agonism and antagonism at beta-adrenoceptors experiments with the enantiomers of terbutaline and pindolol. Acta Pharmacol. Toxicol. (Copenh) 1984, 54, 285-291. 

Borgstrom, L. Kennedy, B.M. Nilsson, B. Angelin, B. Relative absorption of the two enantiomers of terbutaline after duodenal administration. Eur. J. Clin. Pharmacol. 1990, 38, 621-623. 

Borgstrom, L. Liu, C.X. Walhagen, A. Pharmacokinetics of the enantiomers of terbutaline after repeated oral dosing with racemic terbutaline. Chirality 1989, 1, 174-177. 

In capillary electrophoresis (CE), CDs and their ionic and neutral derivatives have been successfully used as additives in the carrier system for the separation of structural isomers and structurally related compounds [53]. The commonly used neutral CDs are the native a-, /3- and y-CDs and the dimethyl, trimethyl, hydroxyethyl and hydroxypropyl forms [54]. The charged CDs are carboxymethyl, sulfobutyl ether, sulfated and amino CDs. The methyl derivatives of the CD are effective in separating chiral compounds, enantiomers of terbutaline, ephedrine and carnitine. The neutral derivatives of hydroxyalkylated /3-CD and the mixture... 

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