Mephenytoin enantiomers

These ptwofactors may influence resolution of isomers in an additive (e.g. mandelic acid enantiomers, ortho and meta cresols) or substractive manner (e.g. mephenytoin enantiomers). Thus for the designing and optimization of resolution one should know the stability constants and adsorption properties of CD complexes with the compounds being separated. 

Figure 9 shows the examples of separations of racemic mixtures of methylphenobarbital and mephenytoin performed under optimal conditions available (37). It has been found that ( -CD complexation resuTts in a distinct enantioselectivity in the case of mephenytoin and barbiturates which have a chiral center in the pyrimidine ring. The resolution of barbiturate enantiomers is due to the different stabilities of their diastereo-isomeric -CD complexes, while the separation of mephenytoin enantiomers results from the difference in their adsorption on the RP phase. The latter case should be considered further. It has been already suggested (18) that the adsorption of CD complexes in which guest molecules are entirely immersed in the CD cavity is low on RP phases. The distinct adsorption arises from the part of the molecule which is outside the cavity. Taking into account this fact and the remarkable difference in the adsorption of -CD mephenytoin diastereoisomers one may conclude that a significant difference must exist between immersion of mephenytoin enantiomers in the -CD cavity. 

Fig. 2-18. Normal phase retention of the first eluted and seeond eluted enantiomer of mephenytoin on vaneomyein CSP (250 x 4.6 mm). The flow rate was 1.0 mL min at ambient temperature (23 °C).

FIGURE 6 Effect of mobile phase composition on the resolution of enantiomers of different racemates in normal phase HPLC on antibiotic CSPs. (a) First ( ) and second ( ) eluted enantiomers of y-phenyl-y-butyrolactone and first ( ) and second (O) eluted enantiomers of 4-phenyl-2-methoxy-6-oxo-2,4,5,6-tetrahydropyridine-3-carbonitrile on Chirobiotic T column and (b) first ( ) and second (O) eluted enantiomers of mephenytoin on Chirobiotic V column. (From Refs. 1 and 21.)... 

Tyrbing et al. [166] studied the stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite in five poor metabolizers, and five extensive metabolizers of 5-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separated enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 h after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+) omeprazole was larger... 

Analytical Properties Resolution of several enantiomers of polycyclic aromatic hydrocarbons, for example, chrysene 5,6-epoxide, dibenz[a,h]anthracene 5,6-epoxide, 7-methyl benz[a]anthracene 5,6-epoxide resolution of barbiturates, mephenytoin, benzodiazepinones, and succinimides direct separation of some mono-ol and diol enantiomers of phenanthrene, benz[a]anthrene, and chrysene ionically bonded to silica gel, this phase provides resolution of enantiomers of c/s-dihydroidiols of unsubstituted and methyl- and bromo-substituted benz[a]anthracene derivatives having hydroxyl groups that adopt quasiequatorial-quasiaxial and quasiaxial-quasiequatorial conformation Reference 31-35... 

Racemic mephenytoin is stereoselectively metabolized in man, with the (S)-enantiomer being rapidly hydroxylated in the 4 -position by CYP2C19 and the (R)-enantiomer being slowly metabolized. The OS )-mephenytoin phenotype (genotypically conferred or by administration of an inhibitor) is determined following an oral dose by measuring the ratio of (5)-mephenytoin to (//(-mephenytoin in the 0- to 8-hour urine (93). 

The anticonvulsant drug mephenytoin exists as two enantiomers (R- and S-). Ktifer reported the stereoselective metabolism of S-mephenytoin in the dog. Later, while studying the metabolism of mephenytoin in humans, Ktifer found that the formation and urinary excretion of the 4 -hydroxymetabolite of mephenytoin is rapid during the first 24 hr after administration of the drug and this metabolite is derived almost entirely from the S-enantiomer. Unexpectedly, one of the human subjects complained of unacceptable sedation on a dose of mephenytoin. From a family study it was determined that metabolism of mephenytoin in the family of the individual who metabolized the drug poorly was inherited as an autosomal recessive trait. Subsequent population studies showed that while -3-5% of Caucasians were PMs, as many as 13-23% of Asians were PMs of mephenytoin. 

Table I. Capacity factors of solutes (kl), calculated capacity factors of their P>-CD complexes (kn.g nn) and stability constants (Kj of -CD complexes of cresoles, p-nitrocinnimic acids and enantiomers of mandelic acid, mephenytoin and hexobarbital. Stationary phase 10 pm LiChrosorb RP 18...

Plots of selectivity factor (calculated using Equation 2 and the data from Table I) for mephenytoin and hexobarbital enantiomers versus CD concentration are shown in Figure 3 a,b (22) The profiles of relation oC vs [(3-CD] for these two compounds are different because two different factors determine resolution of their enantiomers difference in K- values for hexobarbital and difference in kl t ftnn values for mephenytoin. The latter case represents 5nuinteresting example the resolution of its enantiomers arises from the great differentiation in the adsorption of diastereoisomeric (3-CD complexes. The calculated selectivity factor for these complexes is ca 3 (see Table I). In this particular case selectivities of the two processes adsorption and com-plexation in the bulk mobile phase solution are opposite to each other enantioselectivity arising from selective adsorption dominating over differentiation in the solution. Unfortunately the stabilities of diastereoisomeric -CD mephenytoin complexes are relatively small and solubility of -CD in the mobile phase solution is rather limited. Therefore one cannot shift the comple-xation equilibrium... 

Figure 3. Selectivity factor values calculated for (a) mephenytoin (a ) and (b) hexobarbital (a ) enantiomers as a function of log [/3-CD], The full line corresponds to the conditions experimentally available.

The same procedure has been applied for resolution of mephenytoin and some barbiturates into enantiomers (26). 

It seems tc, also be worth mentioning that the described procedure has been used for micro-preparative separations of mephenytoin and hexobarbital enantiomers (26) p -CD solutions were also successfully used for resolution of 1-[2-(3-hydroxyphenyl)-l-phenylethylJ-4-(3-me-thyl-2-buteny1) piperazine enantiomers in RP systems (.20). An especially interesting example of the application of -CD is the separation of optical isomers of D,L - norgestrel (27). 

Figure 18 Enantiomer separation of mephenytoin on a 10-m fused silica capillary with 3-bu-2,6-pe-y-CD 60 40, w/w in OV1701) at 160 C.

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

Some of the greatest differences in the pharmacokinetics of stereoisomers can be attributed to stereoselective hepatic biotransformation. The oral clearance of 5-mephenytoin is 170 times that of the R enantiomer in extensive metabolizers of the drug. ° This large difference in clearance is reflected in a 2-h half-life for the 5-mephenytoin compared to a 76-h half-life for the R enantiomer in the same patient group. Interestingly, the half-life of the S isomer (63 h) and the R isomer (77 h) are similar in poor metabolizers of mephenytoin. Numerous other examples of stereoselectivity in hepatic clearance can be found in the literature. ... 

Sybilska, D. Zukowski, J. Bojarski, J. Resolution of mephenytoin and some chiral barbiturates into enantiomers by reversed phase high performance liquid chromatography via P-cyclodextrin inclusion complexes. J. Liq. Chromatogr. 1986, 9 (6), 591-606. 

The use of CDs with bile salt micelles has been also successful for enantiomer separations. For example, Dns-DL-AAs, baclofen and its analogs, mephenytoin and fenoldopam, naphthalene-2,3-dicarboxaldehyde derivatized dl-AAs (CBI-dl-AAs), diclofensine, ephedrine, nadolol, and other j8-blockers, and binaphthyl-related compounds were enantioseparated by CD-MEKC with bile salts. 

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. 

Table 6 Oral Clearance and Plasma Half-Lives of Propranolol Enantiomers After Oral Administration of the Racemate (80 mg) to Volunteers with Different Phenotypes of Debrisoquine and Mephenytoin Hydroxylation... 

Bile salts are natural and chiral anionic surfactants which form helical micelles of reversed micelle conformation. The first report on enantiomer separation by MEKC using bile salts was the enantioseparation of dansylated DL-amino acids (Dns-o,L-AAs) and, since then, numerous papers have been available. Nonconjugated bile salts, such as sodium cholate (SC) and sodium deoxycholate (SDC), can be used at pH > 5, whereas taurine-conjugated forms, such as sodium taurocholate (STC) and sodium taurodeox-ycholate (STDC), can be used under more acidic conditions (i.e., pH > 3). Several enantiomers, such as diltiazem hydrochloride and related compounds, carboline derivatives, trimetoquinol and related compounds, binaphthyl derivatives, Dhs-dl-AAs, mephenytoin and its metabolites, and 3-hydroxy-l,4-benzodiazepins have been successfully separated by MEKC with bile salts. In general, STDC is considered as the the most effective chiral selector among the bile salts used in MEKC. 

A number of enantiomers (aminoglutethimide, chlorpheniramine, chlorthalidone, fluoxetine, ibuprofen, ketoprofen, methylphenidate, metoprolol, phensuximide, propranolol, suprofen and mephenytoin) were separated on a -cyclodextrin column using 40/60 to 20/80 acetonitrile/water (0.1% triethylammonium acetate pH 4.1 or 7.1) mobile phase (analyte dependent) [1550]. 

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