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.

Sodium butyrate and its synthetic amide derivative modulate nociceptive behaviors in mice

“…Interestingly, in our experimental conditions butyrate-based treatments showed a similar efficacy to that obtained using a potent NSAID, ketorolac [42], or the anti-inflammatory/analgesic compound PEA [20,21,43].…”

D-Galactose as a Vector for Prodrug Design

“…In particular, a ketorolac-galactose conjugate (Ketogal) Fig. (8) has been synthesized and both its pharmacokinetic and pharmacodyamic profiles have been evaluated [64]. Ketorolac is the NSAID that presents the highest risk of toxic reaction, a feature that has drastically limited its use despite its analgesic and anti-inflammatory efficacy.…”

The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges

“…The masking of the active moiety of ketorolac was found essential to prevent the dose-limiting gastrointestinal irritation, a side effect profile of the drug (Curcio et al 2009). A reversible conjugation of ketorolac with D-galactose was performed and the resulted prodrug appeared to deliver similar extent of the active moiety while potentially avoiding gastric irritation and/or ulceration due to the active moiety (Curcio et al 2009).…”

“…A reversible conjugation of ketorolac with D-galactose was performed and the resulted prodrug appeared to deliver similar extent of the active moiety while potentially avoiding gastric irritation and/or ulceration due to the active moiety (Curcio et al 2009). …”