Pharmacokinetic evaluation of caffeine-NSAIDs combinations
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abstract
There are many reports describing the potentiation of analgesic effect of several non-steroidal anti-inflammatory drugs (NSAIDs) by caffeine, although the origins of such potentiation remains unclear. PURPOSE: To evaluate the possible changes in caffeine pharmacokinetics after the co-administration with several NSAIDs in order to test whether potentiation by caffeine of analgesic effect is due to a pharmacokinetic mechanism. METHOD: Male Wistar rats were given caffeine alone (32 mg/kg; po; CAP) or in combination with paracetamol (316 mg/kg; CAP-PAR), ibuprofen (100 mg/kg; CAF-IBU), tolmetin (3 mg/kg; CAF-TOL), and ketorolac (1.8 mg/kg; CAF-KET). Blood samples were drawn before and 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min after drug administration. Caffeine whole blood levels were determined by HPLC. RESULTS: Caffeine maximum plasma concentrations (Cmax) was 43.06 μg/ml when administered alone and was not significantly different from combinations CAP-PAR, CAF-IBU, CAF-TOL (44.58, 32.10, 50.45 ug/ml respectively). However, CAF-KET combination produced a Cmax of caffeine of 31.8 μg/ml that was significantly minor than caffeine alone. On the other hand, the area under the curve (AUC) of caffeine (8104 ug/min/ml) was not different when co-administered with CAF-TOL or CAP-PAR (8998 and 7773 μg/min/ml), but the combination with ketorolac or ibuprofen produced AUCs significantly less, 4786 and 5474 μg/min/ml respectively. CONCLUSION: Caffeine pharmacokinetic processes appear not to explain the potentiation of analgesic effect of combinations of caffeine with TOL and PAR. However, it appears that the changes in some pharmacokinetic parameters for combinations of caffeine with IBU and KET might partially explain such increase.
