Effect of naproxen co-administration on valproate disposition

The effects of co-administration of the antiepileptic agent valproic acid ( VPA) and the non-steroidal anti-inflammatory drug naproxen (NAP) on their r elative dispositions (particularly with respect to glucuronidation) were in vestigated in human volunteers. Seven healthy males received each drug alon e and then in combination (orally twice daily for seven days, 500 mg sodium VPA, 500 mg NAP). On day 7 of each dosing phase, serial plasma and 24 h ur ine samples were collected for analysis. Go-administration of NAP resulted in significant increases (about 20%, p < 0.05) in the apparent plasma clear ance of total VPA and in the unbound fraction of VPA in plasma, with the ap parent plasma clearance of unbound VPA being unchanged. There were associat ed increases in the formation clearances to urinary VFA-glucuronide and 3-o xo-VPA, though these were relatively greater for the glucuronidation pathwa y land remained significant when formation clearances were calculated using the unbound fraction of drug in plasma). The data thus point to a shift to wards glucuronidation as a result of the NAP-induced increase in the unboun d fraction of VPA in plasma. By contrast, VPA coadministration caused a dec rease (of about 10%, p < 0.05) in the apparent plasma clearance of total NA P. Taken in hand with in vitro results showing a VPA-induced displacement ( of about 40%) of NAP from plasma protein binding sites, the data strongly s upport a role for diminished glucuronidation of NAP and its desmethyl metab olite in the presence of co-administered VPA. Copyright (C) 2000 John Wiley & Sons, Ltd.