Stereoselective Metabolism of Inhaled Anesthetics

Many drugs, including the fluorinated anesthetics, are prepared and used therapeutically as racemic mixtures. Clinical experience has confirmed that enantiomeric (i.e., non-superimposable mirror image) forms of drugs may differ in their potency, pharmacologic actions, and toxicities.^{[89] [90] [91] [92]} Such non-superimposable objects are said to be chiral. The most common chiral origin is the presence of an asymmetric center, a carbon atom attached to four different substitute groups. Enantiomers are optically active; a single enantiomeric form rotates the plane of polarized light passing through an aqueous solution of the enantiomer in a clockwise or counterclockwise direction. The International Union of Pure and Applied Chemistry (IUPAC) preferred method for the classification of enantiomers is the Cahn-Perlog-Ingold convention or (R/S) classification. In this system, the four substitutions around the chiral center are assigned priorities depending on atomic number and atomic mass. When looking down the carbon bond to the substituent with the lowest priority, if the other substitutents are ordered from higher to lower in a clockwise direction, the assignment is the (R)-configuration; if counterclockwise, the (S)-configuration is designated.

Whether the clinical use of a single stereoisomer provides significant advantages depends on pharmacokinetic and pharmacodynamic properties of the respective enantiomers. For example, (S)-penicillamine is used to treat Wilson's disease, cystinuria, and rheumatoid arthritis because of toxicities associated with the racemic drug.^[93] The calcium channel blocker (S)-verapamil is 10 to 20 times more potent than (R)-verapamil and appears to be a better antiarrhythmic, antianginal, and antihypertensive agent.^[94] The cardiovascular drug (S)-propranolol is clinically useful as an antihypertensive and antianginal agent, whereas (R)-propranolol, which lacks cardiovascular effects, is useful in the treatment of hypothyroidism. ^{[95] [96]} Ketamine is provided for clinical use as a racemic mixture, although (S)-ketamine has superior efficacy, faster elimination, and recovery characteristics, with fewer side effects, ranging from restlessness and agitation to emergence reactions, compared with racemic ketamine.^[97] (S)-Ketamine is three times more potent than (R)-ketamine as an anesthetic and analgesic agent, and enantiomeric stereoselectivity of hepatic metabolism of ketamine by microsomal enzymes has been demonstrated.^[98] Ropivacaine, the (S)-enantiomer of a bupivacaine homolog, and levobupivacaine [i.e., (S)-bupivacaine] were developed as alternatives to racemic bupivacaine because of its known central nervous system and cardiovascular toxicities. Ropivacaine is less potent than (S)-bupivacaine or racemic bupivacaine in blocking sodium channels, although the anesthetic and analgesic effects of the two drugs are similar.^[99] Perhaps the most infamous example of enantiomeric differences between optical isomers was observed with the drug thalidomide. The

Figure 8-8 (R)- and (S)-enantiomers of halothane.

Commercial halothane is a racemic mixture of the (R)- and (S)-enantiomers ( Fig. 8-8 ). Metabolic studies have shown that racemic halothane undergoes oxidative metabolism catalyzed by CYP2E1 to TFA-Cl, which covalently binds to several hepatic proteins that are believed to be involved in the immune response leading to halothane hepatotoxicity. To investigate whether CYP2E1 catalyzes the metabolism of halothane in a stereoselective fashion, the enantiomers of halothane were prepared and tested in vivo for their ability to form covalently bound TFA-protein adducts in the liver of mice. It was found that halothane underwent stereoselective metabolism, with the (R)-isomer producing significantly greater amounts of TFA-protein adducts in liver than the (S)-isomer ^[101] ( Fig. 8-9 ). Because the anesthetic potency of the isomers appears to be equal, ^[102] these findings suggest that the (S)-isomer of halothane may be a safer inhaled anesthetic agent than the (R)-isomer or the racemic mixture. This idea is supported by the observation that the hepatotoxicity caused by halothane, enflurane, isoflurane, and desflurane is related to their relative degree of oxidative metabolism in vivo to reactive acyl halide metabolites (see Fig. 8-6 ). Because enflurane, isoflurane, and desflurane also contain an asymmetric carbon atom, the potential for stereoselective metabolism exists with these agents. Other researchers have found that the ratio of (R)-enflurane metabolism was 1.9:1 compared with (S)-enflurane metabolism in human liver microsomes.^[60] It has also been demonstrated that optical isomers of isoflurane exhibit a significant difference in anesthetic potency,^[103] differentially increase sleep time in mice,^[104] and exhibit a modest but significant stereoselectivity at the γ-aminobutyric acid A (GABA_A ) receptor.^{[105] [106] [107]} The clinical use of chiral anesthetic drugs as equal mixtures of their enantiomers has been accepted practice in medicine and anesthesia. With increased knowledge and awareness regarding drug toxicities, future anesthetic drugs may be developed and marketed as single, more potent, and potentially less toxic optically active isomers.