Ketamine, enantiomers

Geisslinger, G. Hering, W. Thomann, P. Knoll, R. Kamp, H.D. Brune, K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br. J. Anaesth. 1993, 70, 666 71. 

Williams and Wainer (2002) use examples of two chiral separations to demonstrate their utility in research. In one example, the difference between enantiomers in the competitive displacement of cyclosporine from immobilized P-glycoprotein was studied. In the other, the pharmacokinetic profiles of (+) and (—)-ketamine and (-h) and (—)-norketamine were determined (Williams and Wainer, 2002). 

The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Figure 1-2, Table 1-1). One of these enantiomers, the (S) -) isomer, is a potent B-receptor blocker. The (R)(+) isomer is 100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (-) enantiomer. Unfortunately, the drug is still used as the racemic mixture. 

The pharmacological effects of the R- and 5-enantiomers of ketamine have been compared in 11 subjects who received //-ketamine 0.5 mg and then 5-ketamine 0.15 mg, separated by 1 week (432). Before and after each drug administration they were subjected to a painful stimulus using a nerve stimulator applied to the right central incisor tooth. Pain suppression was equal with the two drugs. The subjects reported more unpleasant psychotomimetic effects with 5-ketamine and more pleasant effects with //-ketamine. Seven of eleven subjects preferred //-ketamine, while none preferred 5-ketamine. These results suggest that the neuropsychiatric effect of ketamine may be predominantly due to the 5-enantiomer, and that //-ketamine may be a better alternative. This study is in direct distinction to earlier work suggesting that //-ketamine is responsible for most of the undesirable neuropsychiatric side effects of ketamine. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

Jones D 1993 Clinical effects of detomidine with or without atropine used for arthrocentesis In horses. Canadian Veterinary Journal 34 296-300 Joo G, Horvath G, Klimscha W et al 2000 The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats. Anesthesiology 93 231-241... 

Many drugs (e.g., warfarin, propranolol, hexobarbiml, glu-lethimide. cyclophosphamide, ketamine, and ibuprof en) often are administered as racemic mixtures in humans. The two enantiomers present in a racemic mixture may differ in pharmacological activity. Usually, one enantiomer tends to be much more active than the other. For example, the (5)(-) enantiomer of warfarin is S times more potent as an oral anticoagulant than the (/ )(+) enantiomer. In some in-... 

Ketamine, a dissociative anaesthetic, is administered as a racemic mixture (present in the parenteral preparation) and is initially metabolized by the liver to AT-desmethylketamine (metabolite I), which in part is converted by oxidation to the cyclohexene (metabolite II) (Fig. 1.5). The major metabolites found in urine are glucuronide conjugates that are formed subsequent to hydroxylation of the cyclohexanone ring. As the enantiomers differ in anaesthetic potency and the enantioselectively formed (metabolite I has approximately 10% activity of the parent drug) interpretation of the relationship between the anaesthetic effect and disposition of ketamine is complicated. On a pharmacodynamic basis, the S(+) enantiomer is three times as potent as the R(-) enantiomer (Marietta et al., 1977 Deleforge et al., 1991), while the enantiomer that undergoes N-demethylation (hepatic microsomal reaction) differs between species (Delatour et al, 1991). Based on the observed minimum anaesthetic... 

Muir, W.W. Hubbell, J.A. (1988) Cardiopulmonary and anesthetic effects of ketamine and its enantiomers in dogs. American Journal of Veterinary Research, 49, 530-534. 

Many of the side effects (e.g. granulocytopenia) encountered with racemic DOPA were not seen with levo-DOPA and therefore can be attributed to the (+)-enantiomer. For this reason the racemate is no longer given. Post-anesthesia reactions to the anesthetic and analgesic agent ketamine are overwhelmingly associated with the R(-) antipode. ... 

Separation of the enantiomers of ketamine metabolites, norketamine and dehydroketamine... 

Due to its greater anesthetic potency and more favorable side effects profile, S-ketamine has supplanted racemate in several European countries [204], In a study examining the utility of the S enantiomer preoperative medication in pediatric patients [204], the enantiomer was given by the rectal route to 40 children with or without midazolam. Another 22 children were premedicated only with midazolam. The authors found that S-ketamine had no advantage over midazolam alone as a preoperative sedative, and that S-ketamine was much less effective than had been observed previously in a similar cohort of subjects given racemic ketamine. The authors speculated [204] that perhaps the enantiomers are absorbed differently by the rectal route of administration. 

Fig. 3 Separation and determination of the enantiomers of ketamine in human plasma by using weak affinity chromatography and a column containing Oj-acid glycoprotein as the stationary phase with detection by mass spectrometry.

The enantiomers of ketamine exhibit differences in pharmacological activities and in metabolism. Kharasch and Labroo [27] studied the in vitro metabolism by liver microsomes of the isolated isomers of racemate. In a separate experiment, they determined the concentrations of the main metabolite NK. This secondary amino compound was treated with PFPA for derivatization. The hexadeuterated NK was used as the internal standard. 

Leung and Baillie [10] studied the stereoselective metabolism of NK in rat liver microsomes using racemic NK and its individual enantiomers (/ -NK and (5) -NK labeled with deuterium on aromatic ring ((. -NK-Dz). Ketamine was used as internal standard and NK and its metabolites were analyzed after PFP derivati-zation as mono or bis PFP derivatives, respectively. They have assessed the production of 4 and 6 hydroxy norketamine (4-OH-NK, 6-OH-NK) by monitoring the two fragment ions at m/z 304 and 306, which correspond to unlabeled and dideuterated NK, respectively. Norketamine was monitored by two fragment ions at m/z 306 and 308 for the unlabeled (./ -enantiomer and the (. -labeled enantiomer, respectively. Norketamine was shown to exhibit stereoselective metabolism since 6 OH NK was preferentially obtained from (. NK, and 4-OH-NK was preferentially obtained from (./ -NK. 

Both R- and 5-enantiomers are analgesic, anesthetic, and sympathomimetic agents differing however in potency and toxicity. 5-ketamine shows greater affinity to opioid receptor and more strongly inhibits catecholamine transport than / -ketamine [35],... 

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