British Journal of Clinical Pharmacology 1985-09-01

The influence of diflunisal on the pharmacokinetics of oxazepam.

A M van Hecken, T B Tjandramaga, R Verbesselt, P J de Schepper

Index: Br. J. Clin. Pharmacol. 20(3) , 225-34, (1985)

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Abstract

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/- 18 ng ml-1 (mean +/- s.e. mean) to 241 +/- 10 ng ml-1 and total area under the plasma concentration-time curve (AUC) significantly decreased from 5536 +/- 819 ng ml-1 h to 4643 +/- 562 ng ml-1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/- 227 ng ml-1 h to 8116 +/- 644 ng ml-1 h and its elimination half-life increased from 10.0 +/- 0.6 h to 13.0 +/- 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/- 2 ml min-1 to 46 +/- 3 ml min-1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml-1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/- 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.