Thioridazine enantiomers

Bhushan, R and D Gupta (2006). HPLC resolution of thioridazine enantiomers from pharmaceutical dosage form using cyclodextrin-based chiral stationary phase. Journal of Chromatography B, 837,133-137. 

Thioridazine enantiomers were extracted from serum and separated on a phenyl-methylurea colunm (2=263nm) using a 45/45/10/0.0075 hexane/dichloro-methane/methanol/1 M methanolic ammonium acetate mobile phase [740]. Resolution vms good and peaks eluted in < 10 min. Analyte peaks were well removed from serum components and detection limits of 50ng/mL woe reported. Additionally, thioridazine and eight of its metabolites (e.g., thioridazine fV-oxide, northioridazine, and thioridazine 5-sulfate and disulfone) were baseline resolved in <12 min using a silica colunm (2 = 254 run) and an 8/1/1 iso-octane/methanol/dichloromethane (0.036% methylamine) mobile phase [741]. 

In addition to the common use of vancomycin and teicoplanin, the use of other antibiotics as chiral selectors in HPLC were limited. Only a few reports are available in the literature dealing with these antibiotics as HPLC CSPs. Armstrong et al. [42] resolved about 230 racemates on the ristocetin A antibiotic covalently bonded to silica gel. The resolution was carried out using the three modes of mobile phases. The results were complimentary to those obtained on vancomycin and teicoplanin CSPs. In another study, the effect of selector coverage and mobile phase composition on enantiomeric resolution with ristocetin A CSP was carried out by Armstrong et al. [43]. Thiostrepton-based CSP was also used to resolve the enantiomers of thioridazine, 2,2,2-trifluoro-l-... 

Pipecolic acid is a component of a number of active drugs, including bupivacaine (38) and thioridazine (72) (Fig. 18.30), which has been efficiently resolved as the racemic n-octyl pipecolate with Aspergillus niger. The S-iso-mer is obtained as the free acid in a 40%yield based on the available enantiomer with a 97% ee(121). 

Mianserin enantiomer concentrations are also influenced, in a stereoselective fashion, by coadministration of the chiral antipsychotic drug, thioridazine, an inhibitor of CYP2D6 [142]. Steady-state plasma concentrations of the S(-l-)-, but not the R(—)-enantiomer, were significantly increased in depressed Japanese patients (about twofold) by the coadministration of thioridazine. At the same time, there were significant increases in plasma concentrations of both R and S enantiomers of desmethylmianserin, which also possess pharmacological activity, after addition of thioridazine. The authors [142] concluded that the S-enantiomer of the parent drug and both enantiomers of desmethylmianserin are likely substrates for CYP2D6. 

Eap, C.B. Guentert, T.W. Schaublin-Loidl, M. Stabl, M. Koeb, L. Powell, K. Baumann, P. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin. Pharmacol. Ther. 1996, 59, 322-331. 

Yasui, N. Tybring, G. Otani, K. Mihara, K. Suzuki, A. Svensson, J.O. Kaneko, S. Effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and its active metabolite, desmethylmianserin, in depressed Japanese patients. Pharmacogenetics 1997, 7, 369 374. 

---