Pharmacokinetics Effect of Diclofenac or Ketorolac-methyl Eugenol and Their Implication in the Gastroprotection

Leticia Cruz-Antonio, María Elena Sánchez-Mendoza, Yaraset López-Lorenzo, Héctor Isaac Rocha-González, Aida Robles-Sánchez and Jesús Arrieta

Background and Objective: Gastric ulcers are a global health problem, in part caused by the frequent administration of NSAIDs. To reduce gastrointestinal damage, these drugs are often co-administered with gastroprotective agents, which also have severe adverse effects. The objective of this study was to evaluate the protective activity of methyl eugenol against diclofenac- and ketorolac-induced gastric damage and explore the pharmacokinetics of a possible drug interaction of the combined treatments. Materials and Methods: Rats were orally administered methyl eugenol at different doses and 1 h later given diclofenac (80 mg kg^–1) or ketorolac (35 mg kg^–1). The control groups were treated with diclofenac or ketorolac only. After 4 or 6 h, respectively, the animals were sacrificed and the stomachs removed. Gastric damage was quantified to calculate the percentage of gastroprotection. Additionally, a pylorus ligation was performed to test for an anti-secretory effect of methyl eugenol. Other animals received 10 mg kg^–1 of diclofenac or ketorolac with or without methyl eugenol co-administration (100 mg kg^–1) to analyze possible drug interactions. The plasma concentrations of diclofenac and ketorolac were determined by HPLC and pharmacokinetics parameters were assessed. Results: Methyl eugenol decreased gastric lesions induced by diclofenac and ketorolac, achieving the maximum protection of 74.4 and 49.0%, respectively, at 100 mg kg^–1. No anti-secretory activity was detected. With the co-administration of methyl eugenol, the bioavailability of diclofenac was unchanged but that of ketorolac declined. Conclusion: Methyl eugenol provided greater protection against diclofenac- than ketorolac-induced gastric lesions. It affected the bioavailability of ketorolac (due to alterations in absorption) but not that of diclofenac.

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