title: Galactosyl prodrug of ketorolac: synthesis, stability, and pharmacological and pharmacokinetic evaluations.
abstract: Although ketorolac is one of the most potent anti-inflammatory and analgesic drugs, its use has been strongly limited owing to the high incidence of adverse effects reported, particularly in the gastrointestinal tract. Using the prodrug approach, which allows the reduction of toxicological features of the parent drug without altering its pharmacological properties, we synthesized an orally administrable prodrug of ketorolac by means of its reversible conjugation to D-galactose (ketogal). In a single dose study, its pharmacokinetic profile was compared with that of ketorolac. Moreover, we found that this prodrug was able to maintain the anti-inflammatory and the analgesic activity of the drug without giving rise to gastric ulcer formation. Thus, these results indicate that ketogal is a highly effective and valid therapeutic alternative to ketorolac itself.
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Via Domenico Montesano 49, 80131, Naples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Curcio
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.forename: Daniela
authors.initials: D
authors.lastname: Melisi
authors.forename: Maria
authors.initials: M
authors.lastname: Nieddu
authors.forename: Giovanna
authors.initials: G
authors.lastname: La Rana
authors.forename: Roberto
authors.initials: R
authors.lastname: Russo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gavini
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Boatto
authors.forename: Enrico
authors.initials: E
authors.lastname: Abignente
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rimoli
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D005690:Galactose / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D020910:Ketorolac / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D010146:Pain / Q000139:chemically induced; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013276:Stomach Ulcer / Q000139:chemically induced; D013997:Time Factors
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D005690:Galactose; D020910:Ketorolac