title: Chiral kinetics and dynamics of ketorolac.
abstract: It has been shown that the analgesic and cyclooxygenase inhibitor activity of ketorolac tromethamine (KT), which is marketed as the racemic mixture of (-)S and (+)R enantiomers, resides primarily with (-)S ketorolac and that the ulcerogenic activity of this agent also resides in (-)S ketorolac. Resolution of individual enantiomers for analysis in plasma samples has been accomplished by two methods: derivatization to form diastereomers that are separated by HPLC, or direct HPLC using a chiral phase column. When mice and rats were given oral solutions of (-)S and (+) KT, it was found that the kinetics and interconversion of the enantiomers were species and dose dependent. Interconversion was higher in mice than in rats; when (-)S KT was administered, 71% of the area under the concentration-time curve (AUC) was due to (+)R ketorolac in mice, compared with 12% in rats. More interconversion was observed at higher doses; the percent of AUC due to (-)S ketorolac when (+)R KT was administered increased from 12% to 25% in mice and from 2% to 8% in rats. In general, more interconversion occurred from (-)S to (+)R ketorolac in the animal studies. Human subjects were given single oral solution doses of racemic KT (30 mg), (-)S KT (15 mg), and (+)R KT (15 mg). The plasma concentrations of (-)S ketorolac were lower than (+)R ketorolac at all sample times after racemic KT (22% of the AUC was due to (-)S ketorolac). When (+)R KT was administered, (-)S ketorolac was not detectable and interconversion was essentially 0%. When (-)S KT was administered, significant levels of (+)R ketorolac were detectable and interconversion was 6.5%. After all doses, plasma half-life was shorter and clearance greater for (-)S ketorolac than for (+)R ketorolac. Thus, in humans very little or no interconversion of (+)R to (-)S was observed, and interconversion of (-)S to (+)R was minimal (6.5%). These data demonstrate that the kinetics and interconversion of the enantiomers of ketorolac is different in animals and humans as well as from most other NSAIDs. This may be due to more rapid excretion or metabolism of (-)S ketorolac and a different mechanism of interconversion.
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mroszczak
authors.forename: D
authors.initials: D
authors.lastname: Combs
authors.forename: M
authors.initials: M
authors.lastname: Chaplin
authors.forename: I
authors.initials: I
authors.lastname: Tsina
authors.forename: T
authors.initials: T
authors.lastname: Tarnowski
authors.forename: C
authors.initials: C
authors.lastname: Rocha
authors.forename: Y
authors.initials: Y
authors.lastname: Tam
authors.forename: A
authors.initials: A
authors.lastname: Boyd
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: L
authors.initials: L
authors.lastname: Depass
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D020910:Ketorolac; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D051381:Rats; D013237:Stereoisomerism; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D014046:Tolmetin; D020910:Ketorolac