Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers

Objective: The effects of coadministration of the non-steroidal anti-inflam matory drug diflunisal (DF) on glucuronidation and P-oxidation of the antie pileptic agent valproic acid (VPA), and of VPA on DF glucuronidation, were studied in human volunteers. Methods: Seven healthy male volunteers received sodium valproate (NaVPA, 20 0 mg) orally twice daily for 7 days, after which all drug intake ceased for 1 month. The volunteers then took DF (250 mg) orally twice daily for 7 day s. Both drugs were then taken (at the same doses as previously) twice daily for 7 days. On day 7 of each dosing phase, serial blood samples and all ur ine passed over the 12-h inter-dosing interval were collected. VPA, DF and selected metabolites were analysed using validated methods. Statistical com parisons of pharmacokinetic parameters were made using paired Student's t-t ests. Results: Mean plasma concentrations of total VPA were lower and apparent pl asma clearances significantly higher during DF coadministration. This was a ssociated with a significant 20% increase in the unbound fraction of VPA (f rom 6.6 +/- 1.3% to 7.9 +/- 1.8%). The apparent clearance of unbound VPA wa s not different. There was no evidence of any significant effect of DF coad ministration on VPA metabolism: urinary recoveries of and formation clearan ces to urinary VPA-glucuronide, E-2en-VPA, 3-oxo-VPA and 4-en-VPA were not significantly altered. However, there was a highly significant 35% increase in the area under the plasma concentration-time curve from 0-12 h (AUC(0-1 2)h) Of 3-oxo-VPA and its renal clearance was lower, though not significant ly so. VPA coadministration had no effect on DF pharmacokinetics or formati on clearances of DF to its acyl glucuronide (DAG), phenolic glucuronide (DP G) or sulfate (DS) conjugates. However, plasma AUC(0-12h) values of the glu curonides were significantly lower and their renal clearances higher (thoug h significantly so only in the case of DPG) during VPA coadministration. Conclusions: Steady-state coadministration of VPA and DF leads to a signifi cant displacement of VPA from plasma protein binding sites. There was no ev idence of competition for glucuronidation capacity or other metabolic inter actions. Rather, the interactions detected appeared to be renal in nature, with renal clearance of 3-oxo-VPA being reduced by DF coadministration, and renal clearance of DPG and perhaps DAG being increased by VPA coadministra tion.