Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam

Abstract

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.