title: Permeability of ketorolac acid and its ester analogs (prodrug) through human cadaver skin.
abstract: The in vitro skin permeabilities of ketorolac acid (KA), a potent nonsteroidal analgesic, and its two ester analogs as prodrug through human cadaver skin were investigated. The two esters of KA, namely, the ethyl ester (KEE) and [(N,N-dimethylamino)carbonyl]methyl ester (KDAE), were selected. The melting temperature of the two esters was significantly lower than that of ketorolac free acid. The partition coefficients (KO/W) were 600, 3541, and 124 for KA, KEE, and KDAE, respectively. The enzymatic hydrolysis of KEE and KDAE by human pooled serum at 37 degrees C was investigated. The esters were hydrolyzed to KA by the serum esterases; the metabolic rate constants were 0.0418 and 0.0148 min-1 for KDAE and KEE, respectively. The serum half-life of KDAE was about 3 times shorter than KEE. When split-thickness cadaver skin was incubated with ester solution at 32 degrees C, the enzymatic hydrolysis of these esters was observed. The metabolic rate in the skin, however, was significantly lower than in the human pooled serum. The skin permeations of KA, KEE, and KDAE through heat-separated epidermis from propylene glycol (PG), PG/glyceryl monocaprylate (GMC) (9:1), and PG/Azone (19:1) vehicle mixtures were evaluated using modified Franz flow-through diffusion cells. The skin fluxes of KA, KEE, and KDAE from PG/GMC (9:1) were 50 +/- 10, 15 +/- 4, and 57 +/- 6 micrograms/cm2/h, respectively. KA was detected in the receiver compartment, albeit to a lesser extent. In conclusion, KDAE appeared to be a better ester prodrug than KEE because it exhibited relatively higher skin flux and faster enzymatic hydrolysis by human serum to liberate the parent drug.
authors.affiliation: Syntex Research, Palo Alto, California 94304.
authors.forename: S D
authors.initials: SD
authors.lastname: Roy
authors.forename: E
authors.initials: E
authors.lastname: Manoukian
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D020910:Ketorolac; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D012869:Skin Absorption; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D014046:Tolmetin; D020910:Ketorolac