Synergistic inhibition of muscarinic signaling by ketamine stereoisomers and the preservative benzethonium chloride.
BACKGROUND
Ketamine (Ketalar; Parke-Davis, Morris Plains, NJ) has been shown to inhibit muscarinic signaling with a median inhibitory concentration (IC50) of 5.7 microM. Whereas Ketalar is a racemic mixture, recent interest has focused on clinical use of the S(+) ketamine isomer, which is three times as potent an analgesic as the R(-) isomer yet seems to be associated with fewer psychoactive side effects. Therefore, the authors studied the effects of S(+) and R(-) ketamine and the preservative benzethonium chloride on muscarinic signaling.


METHODS
Rat ml muscarinic acetylcholine receptors were expressed recombinantly in Xenopus laevis oocytes. Ca2(+)-activated Cl- currents in response to 10(-7) M acetyl-beta-methylcholine were determined by two-electrode voltage clamping in the presence of various concentrations of ketamine and benzethonium. Concentration-inhibition curves were constructed and used for algebraic and isobolographic analysis.


RESULTS
The IC50. was 125 +/- 33 microM for S(+) ketamine, and 91 +/- 19 microM for R(-) ketamine. This difference was not statistically significant, indicating that muscarinic inhibition by ketamine is not stereoselective. The R(-)/S(+) mixture had an IC50 of 48 +/- 1 microM, and thus the stereoisomers interact synergistically. When appropriate concentrations of benzethonium were added, an IC50 of 15 +/- 2 microM resulted.


CONCLUSIONS
The muscarinic inhibitory action of ketamine isomers is not stereoselective. Because S(+) ketamine is a significantly more potent analgesic, it should have less muscarinic inhibitory action than R(-) ketamine when used in clinically equivalent doses. A significant fraction of the muscarinic inhibitory action of Ketalar is due to the preservative benzethonium. If reconstituted with a different preservative, Ketalar might be a less potent muscarinic antagonist.
Durieux
M E
ME
University of Virginia Health Sciences Center, Charlottesville 22906-0010, USA. med2p@virginia.edu
Nietgen
G W
GW
D000818:Animals; D001558:Benzethonium / Q000494:pharmacology*; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007649:Ketamine / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D011310:Preservatives, Pharmaceutical / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D011310:Preservatives, Pharmaceutical; D011976:Receptors, Muscarinic; D001558:Benzethonium; D007649:Ketamine