Role of racemization in optically active drugs development

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454 ALI ET AL. TABLE 1. Harmful effects of racemization of optically active drugs Optically active drugs Therapeutic group Species Harmful effects ( )-Thalidomide Immunomodulatory Man Malformation of embryos & antiangiogenic in pregnant woman 2 ( )-Ibuprofen Antianalgesic Man Inactive 2 D-DOPA Parkinson’s disease Man Inactive 8 L-Sucrose Sweeting agent Man Non-metabolized 9 D-Ribose sugar Sugar Man Less therapeutics 10 L-Penicillamine Antiarthritic Man Toxic 2 (þ)-Warfarin Anticoagulant Man Inactive 2 L-Peptide (V13KD) Antimicrobial Candida ablicans Trypsin proteolysis 11 S-Albuterol Adrenergic Rat Partially active 12 (þ)-Clausenamide Synaptic transducer Rat Low synaptic Transmission 13 S-Propranolol b-Blockers Man Toxic 14 R-Ketoprofen Antiallodynic Man Inactive 15 R-( )-Vigabatrin Antiepileptic Man Highly toxic 16 S-Tiaprofenic acid NASID Man Inactive 17 N-Alkylated Antitumor & antimetastic Man Inactive 18 dihydro-pyridine-( )-AC 394 (þ)-Tramadol Analgesic Man Nausea & vomiting 19 R-CC-4047 Immunomodulatory Man Inactive 5 (þ)-Thyroxine Hormone Man Inactive 2 S-Flurbiprofen NSAID Man Inactive 20 ( )-Ketamine Anesthetic Rat Inactive 2 (þ)-Methadone Analgesic Man Inactive 2 (þ)-Morphine Analgesic Man Inactive 2 ( )-Tetramisole Anthelmintic Man Inactive 2 S-2-[2,6-dioxopiperidine-3-yl]-phthalimidine Sedative Monkey Teratogenic 4 R-Fenoprofen NSAID Rat Inactive 6 ( )-Fluoxetine Anti-depressant Man Inactive 2 (þ)-Verapamil Calcium channel blocker Man Inactive 2 NASID: Non steroidal anti-inflammatory drug. very important information in medicinal and clinical sciences. And many authorities are asking data on the harmful effects of enantiomers. But unfortunately, much work could not be done in this direction and is under progress. A warn example is of ( )-thalidomide which is teratogenic in nature. 2,3 It is interesting to mention that the stereoselectivity of teratogenic properties of thalidomide (S-thalidomide as teratogenic enantiomer) had been observed only after intaperitoneal application, and this result still needs to be reconfirmed. L-Penicillamine is more toxic than its Dform. R-( )-Vigabatrin is highly toxic in comparison to its enantiomers. S-2-[2,6-dioxopiperidine-3-yl]-phthalimidine (EM 12) was found to be teratogenic in nature. 4 Besides, some enantiomers are inactive as for example Teo et al. 5 reported R-enantiomer of CC-4047 as less effective in human. Similarly, Berry and Jamali 6 reported R-( )fenoprofen as inactive antipode. Yoshida et al. 7 reported that S-enantiomer of KE-298 reflected twofold greater area under curve (AUC) value (drug plasma concentration with time) than R-enantiomers after oral dosage in rats. The different therapeutic properties of some drug enantiomers are summarized in Table 1. RACEMIZATION OF OPTICALLY ACTIVE DRUGS As indicated earlier the knowledge of racemization of optically active drugs is essential to provide safe dosage to Chirality DOI 10.1002/chir human beings. Therefore, it is customary to study first the racemization in vitro followed by in vivo and, hence, the racemization of optically active drugs is discussed in the two sections i.e. in vitro and in vivo. Reist et al. 21 described the meaning and importance of racemization, enantiomerization, diastereomerization, and epimerization. The authors defined the racemization as a macroscopic and statistical reaction of irreversible change of one enantiomer into the racemic form. And enantiomerization is a microscopic process of reversible change of one enantiomer into other. Wsol et al. 22 reviewed the chiral inversion of drugs and discussed coincidence and principle of this phenomenon. The authors discussed chiral inversion of 2-arylpropionic acid derivatives. Effect of various parameters on the chiral inversion and its mechanisms was also highlighted. In Vitro Racemization The racemization in test tube is called as in vitro racemization, which provides rough knowledge of the behavior of optically pure drugs. However, some workers studied in vitro racemization of optically active drugs, which is discussed herein. The study of ketorolac racemization was performed by Brandl et al. 23 in aqueous solution at 258C and 808C temperatures and reported a U type pH rate outline at 808C. The authors also reported a T 90 value of the drug in a solution of 1.5% (R)-ketorolac tromethamine at pH 7.4 and 258C temperature. Aso et al. 24 reported the
Fig. 1. The effect of cofactors on the inversion of R-ibuprofen with rat liver homogenate. (*P ¼ 0.0002 decrease in R-ibuprofen concentration, **P ¼ 0.0008 increase in S-ibuprofen concentration). 20 effects of a-, b-, g- and dimethyl-b-cyclodextrins (CDs) and liposomes on epimerization and racemization of chiral drugs such as etoposide, ethiazide, and carbenicillin. The rate of epimerization of carbenicillin increases with a- and b-CDs but no effect was observed on epimerization of etoposide and ethiazide. Dimethyl-b-cyclodextrin diminishes the epimerization of etoposide and ethiazide but does not affect epimerization of carbenicillin. g-CD decreases and increases the epimerization of etoposide and of carbenicllin respectively. The authors indicated that inclusion complexes are responsible for the retardation of racemization as CDs prevented the attack by bases and buffers. The polymyxins B and E have complex structures of polypeptide antibiotics. Polymyxin B contains B 1,B 2,B 3, and B 4 components as major 25 while isoleucine-polymyxin B 1 26 and polymyxin B5 and B 6 27 are minor constituents. Similarly, polymyxin E 1 (colistin A) and polymyxin E 2 (colistin B) are the main parts of polymyxin E whereas polymyxin E 3 and E 4, 25 norvaline-polymyxin E 1, valinepolymyxin E2, 26 valine-polymyxin E1, isoleucine-polymyxin E 1 and isoleucine polymyxin E 2 28 are minor identities. Orwa et al. 27 described the decomposition of polymyxin with racemization as the principal mechanism of decomposition at pH 1.4 and 7.4 pH. The traits of decomposition were studied in aqueous solution at different pHs and temperatures. At constant pH and temperature it was found that the decomposition kinetics of polymyxins follows pseudo first order kinetics. Knihinicki et al. 20 studied the racemization of R-ibuprofen in rat liver homogenate in the presence of ATP, CoA and (ATP and CoA both) and in the absence of ATP and CoA both for 30 min at 378C separately and respectively. A remarkable change occurred in the concentration of Rand S-ibuprofen enantiomers in the presence of both ATP and CoA together (see Fig. 1). The inversion of R-ibuprofen was not reported into kidney and intestine homogenates of rat under the above cited four conditions. R-Ibuprofen was mixed with rat liver homogenates having cofactors and was observed a decrease in the concentration of R-ibupro- RACEMIZATION IN OPTICALLY ACTIVE DRUGS DEVELOPMENT 455 fen after 10 min. No decrease was observed in the concentration of R-ibuprofen in absence of CoA. The racemization of R- and S-ibuprofen-CoA in buffer {TRIS HCl [tris-(hydroxymethyl) methylamine hydrochloride)] 50 mM, pH 7.4} and in fresh human plasma is shown in Figures 2a and 2b, which indicates the different pattern of racemization under varying conditions. Other authors also reported the inversion of R-ibuprofen in guinea pigs 29 with the observation of stereospecific inversion by CoA. Caldwell et al. 30 also reported the spontaneous racemization of Ribuprofen-CoA. In 1989, Knihinicki et al. 20 studied in vitro racemization of (R)-ibuprofen only. Furthermore, Knihinicki et al. 31 carried out the racemization of R- and S-enantiomers of 2-arylpropionic acids. The racemization and hydrolysis processes in vitro condition have been performed using rat liver homogenate and subcellular fractions. The authors reported that the rat liver homogenate showed racemization of (R)-ibuprofen-CoA to (S)-ibuprofen-CoA Fig. 2. The racemization of R- andS- ibuprofen-CoA in (a) buffer (tris HCl, 50 mM, pH 7.4) and (b) fresh human plasma. [R-Ibuprofen (*), Sibuprofen (l) after mild alkaline hydrolysis and R-ibuprofen concentrations (D) before alkaline hydrolysis.] 16 Chirality DOI 10.1002/chir
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