Pharmacokinetics and bioavailability of intravenou

Authors: R Jochemsen J J H Hogendoorn J Dingemanse J Hermans J K Boeijinga D D Breimer

Publish Date: 1982/06/01

Volume: 10, Issue: 3, Pages: 231-245

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Abstract

The pharmacokinetics and bioavailability of nitrazepam following intravenous oral tablet and rectal solution administration were studied in seven healthy young male volunteers Nitrazepam plasma concentrations were determined by electroncapture GLC pharmacokinetic evaluations were made by compartmental analysis NONLIN and compared with the results obtained by a less stringent modelling of the data The plasma concentrationtime profile was similar for all three routes of administration Mean kinetic parameters as obtained by compartmental analysis of iv nitrazepam were distribution halflife 17 min volume of distribution after equilibrium 214 liters/kg total plasma clearance 616 ml/min elimination halflife 290 h The mean protein unbound fraction of nitrazepam in plasma was 123 and the clearance of the unbound fraction was 506 ml/min Absorption of oral nitrazepam started after the elapse of a lag time mean value 12 min and occurred as an apparent firstorder process in all but one subject with a mean absorption halflife of 16 min Distribution and elimination halflives were comparable with those following iv administration Following rectal administration of the nitrazepam solution rapid firstorder absorption occurred with a mean lag time of 4 min and a mean absorption halflife of 9 min Peak times median 18 min were significantly shorter than following oral administration median 38 min but there was little difference in peak concentrations The distribution halflife was similar to iv and oral administration but the elimination halflives were longer with a mean value of 331 h Following iv administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data Following oral and rectal administration a good agreement between the two procedures was found for the elimination halflife estimation of bioavailability however was higher by compartmental analysis The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20 lower when it is given rectally but considerable interindividual differences were observed

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